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The Landmark Series

The Annals of Surgical Oncology’s, The Landmark Article Series, has quickly become a leading resource that demonstrates the logical progression of clinical trials and key evidence leading up to current multidisciplinary therapy. Articles and links to abstracts are listed below.

SSO Mobile users: You may download articles by visiting the Annals of Surgical Oncology link on the app.

Breast Cancer

Carla S. Fischer, MD, Julie A. Margenthaler, MD, Kelly K. Hunt, MD and Theresa Schwartz, MD

The evolution in axillary management for patients with breast cancer has experienced multiple dramatic changes over the past several decades. The end result has been an overall de-escalation of surgery in the axilla. Here are reviewed the landmark trials that have formed the basis for our current treatment guidelines. Ann Surg Oncol 27, 724 – 729 (2020).

https://doi.org/10.1245/s10434-019-08154-5

Roberto A. Leon-Ferre MD, Tina J. Hieken MD, and Judy C. Boughey MD

While historically breast cancer has been treated with primary surgery followed by adjuvant therapy, the delivery of systemic therapy in the neoadjuvant setting has become increasingly common, especially for triple-negative and HER2-positive breast cancer. The initial motivations for pursuing neoadjuvant chemotherapy (NAC) were decreasing the tumor burden in the breast and axilla to enable de-escalation of surgery, and use the strategy to advance drug development. While these remain of interest, recent trials have additionally demonstrated survival advantages from escalation of systemic treatment in patients with residual disease, and new studies are testing de-escalation of systemic therapy based on pathologic response. Thus, response information to NAC has become pivotal to guide adjuvant treatment recommendations, and has resulted in NAC being the preferred approach for most HER2-positive and triple-negative breast cancers. Herein, we review select landmark trials that have paved the way for the use of chemotherapy in the neoadjuvant setting for breast cancer.

https://link.springer.com/article/10.1245/s10434-020-09480-9

Leisha C. Elmore, MD, Jill R. Dietz, MD, Terence M. Myckatyn, MD, and Julie A Margenthaler, MD

Despite advances in medical therapy, the foundation of breast cancer treatment is surgery. The landscape of operative intervention for breast cancer has shifted toward less invasive techniques, resulting in improved cosmesis and lower morbidity while maintaining oncologic integrity. In this article, we review the body of literature contributing to landmark advances in mastectomy for the treatment of breast cancer.

https://link.springer.com/article/10.1245/s10434-020-09052-x

Colorectal Cancer​

Salvador Alonso, MD and Leonard Saltz, MD

Micrometastatic disease that is present at the time of surgery is responsible for the overwhelming majority of deaths in patients with what is otherwise perceived to be local and regional colon cancer. The goal of perioperative therapy is to eliminate microscopic residual disease that would otherwise be left behind following surgery. A secondary goal specific to neoadjuvant (preoperative) therapy is to downstage tumors deemed potentially not amenable to an R0 resection on the basis of a suspected T4b primary (locally invading into a surrounding structure). In this landmark series paper, we review the current standard for perioperative therapy in patients with colon cancer.

https://link.springer.com/article/10.1245/s10434-020-09375-9

Yoshikuni Kawaguchi, MD and Jean-Nicolas Vauthey, MD

In the past 20 years, we have seen the following advancements on management of metastatic colorectal cancer. Surgical technique, including staged hepatectomy for bilobar colorectal liver metastases (CLM) was refined, understanding of surgical complexity and genetic heterogeneity of CLM was improved, and effective medical therapies, including oxaliplatin-containing and irinotecan-containing regimens, and molecular-targeted therapies became available.1,2,3,–4 Resection of CLM remains the only curative treatment for this patient group. However, the recurrence rate is high, approximately 70%, in patients undergoing CLM resection.3 To improve survival after CLM resection, randomized control trials (RCT) to evaluate the effect of perioperative chemotherapy and postoperative adjuvant chemotherapy were reported.

 https://link.springer.com/article/10.1245/s10434-020-08809-8

Gastrointestinal Cancer​

Emily Z. Keung, MD, Chandrajit P. Raut, MD, and Piotr Rutkowski, MD, PhD

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Complete resection is the only potentially curative treatment, although recurrence is common, occurring in approximately 40–50% of patients. The introduction of effective molecularly targeted therapies for GISTs has dramatically changed the clinical management paradigms for, and prognosis of, patients with intermediate- and high-risk GISTs, as well as those with locally advanced and metastatic disease. In this article, we review landmark studies that evaluated the use and efficacy of the tyrosine kinase inhibitors imatinib and sunitinib in the adjuvant and neoadjuvant settings for resectable primary and limited resectable metastatic GISTs.

https://link.springer.com/article/10.1245%2Fs10434-020-08869-w

Gynecologic

Derman Basaran, MD and Mario N. Leitao Jr., MD

Cervical cancer incidence and mortality have declined in developed countries during the past few decades as a result of screening programs and vaccination. However, it remains a significant cause of cancer-related mortality in young women. Early-stage cervical cancer, defined as disease limited to the cervix, has traditionally been treated with abdominal radical hysterectomy via laparotomy. Although most early-stage cervical cancers can be cured with open radical hysterectomy, the morbidity associated with open radical hysterectomy is significant compared with simple extrafascial hysterectomy. Since the early 1990s, minimally invasive surgery has been explored for the treatment of this disease, with the goal of minimizing the morbidity associated with open surgery, as reported for endometrial cancer surgery. This report reviews the landmark studies describing and evaluating minimally invasive surgery in the treatment of patients with early-stage cervical cancer.

https://link.springer.com/article/10.1245/s10434-020-09265-0

Head and Neck

Hepatobiliary Cancer​

Jordan M. Cloyd, MD, Aslam Ejas, MD, MPH, and Timothy M. Pawlik, MD, MPH, MTS, PhD

Intrahepatic cholangiocarcinoma is an aggressive biliary tract cancer with distinct anatomic, molecular, and clinical characteristics that distinguishes it from other biliary tract cancers. In this Landmark Series review, we highlight the critical studies that have defined the surgical management of ICC, as well as several randomized controlled trials that have investigated adjuvant therapy strategies. Ann Surg Oncol (2020).

https://doi.org/10.1245/s10434-020-08621-4

Adrianna C. Gamboa, MD, MS and Shishir K. Maithel, MD

This Landmark Series reviews the diagnosis, presentation, and management of gallbladder cancer and specifically discusses the surgical approach and guidelines for adjuvant therapy and explores future studies for delivering neoadjuvant therapy prior to re-resection for incidentally discovered gallbladder cancer. Ann Surg Oncol (2020).

https://doi.org/10.1245/s10434-020-08654-9

Jin He MD, PhD, FACS, Richard D. Schulick MD, MBA, FACS, and Marco Del Chiaro MD, PhD, FACS

The definition of Borderline Resectable Pancreatic Cancer (BRPC) should include anatomic, biological, and conditional component. Neoadjuvant chemotherapy and surgery are associated with improved outcomes of BRPC. Future studies of BRPC should focus on novel biomarkers to guide individualized therapy.

https://link.springer.com/article/10.1245/s10434-020-09535-x

Mary Dillhoff MD, MS and Timothy M. Pawlik MD, MPH, MTS, PhD

Pancreatic cancer is a lethal disease, with nearly 49,000 deaths in the US in 2020.1 Even following curative-intent resection, recurrence and mortality remain high. As such, there has been interest in extending the extent of surgery in an attempt to increase survival. In particular, the role of ‘extended’ versus ‘traditional’ lymphadenectomy has been rigorously debated.2 The prognostic value of lymphadenectomy to determine nodal status, number of metastatic nodes, and lymph node ratio has been well established as an important prognostic indicator of outcomes. However, the impact of extent of lymphadenectomy on recurrence and overall survival remains more controversial.

https://link.springer.com/article/10.1245/s10434-020-09577-1

Jony Van Hilst MD, PhD, Nine de Graaf MD, Mohammad Abu Hilal MD, PhD and Marc G. Besselink MD, PhD

Pancreatic resections are among the most technically demanding procedures, including high risk of potentially life-threatening complications and outcomes strongly correlated to hospital volume and individual surgeon experience. This study reviews and summarizes the available randomized controlled trials evaluating the role of minimally invasive approaches (both robot-assisted and laparoscopic) for pancreatic resections.

https://link.springer.com/article/10.1245/s10434-020-09335-3

Flavio G. Rocha MD, FACS, FSSO

Pancreatic cancer is one of the most aggressive gastrointestinal malignancies despite multimodality therapy. In the last several years, genomic studies have revealed that carcinogenesis is driven largely by key driver mutations that can be targeted for oncologic therapy. In addition, advances in cancer immunology have identified receptors and monoclonal antibodies that can be manipulated into harnessing the power of the host’s immune system for antitumor treatment. These strategies have generated a paradigm shift in the management of several cancer types, including those in the gastrointestinal tract. However, there are several complicating factors when translating the results to pancreatic cancer, including the dense, fibrotic stroma unique to this disease that may shield the cancer cells from both cytotoxic and immunologic agents. Although the majority of trials have been performed in the metastatic setting, this review will focus on both the historic studies that have defined this field as well as the emerging data arising from ongoing efforts to exploit newly discovered mutations and their druggable targets.

https://link.springer.com/article/10.1245/s10434-020-09367-9

George Van Buren II, MD and Charles M. Vollmer Jr., MD

Pancreatic fistula has been the defining complication and challenge of pancreatic surgery. Better awareness and mitigation of postoperative pancreatic fistulas has led to significant improvements in morbidity and mortality of pancreatic surgery. The definition and management of pancreatic fistulas has sequentially progressed over the last three decades; the literature ranges from retrospective, observational studies to prospective multicenter randomized controlled trials. The landmark literature contributions driving the perioperative management of pancreatic fistulas are detailed in this article.

Jordan M. Cloyd, MD and George A. Poultsides, MD, MS

Pancreatic neuroendocrine tumors (PNETs) comprise a heterogeneous group of neoplasms arising from pancreatic islet cells that remain relatively rare but are increasing in incidence worldwide. While significant advances have been made in recent years with regard to systemic therapies for patients with advanced disease, surgical resection remains the standard of care for most patients with localized tumors. Although formal pancreatectomy with regional lymphadenectomy is the standard approach for most PNETs, pancreas-preserving approaches without formal lymphadenectomy are acceptable for smaller tumors at low risk for lymph node metastases. Furthermore, observation of small, asymptomatic, low-grade PNETs is a safe, initial strategy and is generally recommended for tumors < 1 cm in size. In this Landmark Series review, we highlight the critical studies that have defined the surgical management of PNETs.

https://link.springer.com/article/10.1245/s10434-020-09133-x

Melanoma and Non-Melanoma Skin Cancers​

Georgia M. Beasley, MD, Jonathan S. Zager, MD and John F. Thompson, MD

In-transit melanoma represents a distinct disease pattern in which melanoma recurs as dermal or subcutaneous nodules between the primary melanoma site and the draining regional lymph node basin. The disease pattern is often not amenable to complete surgical resection. Here are reviewed landmark studies describing and evaluating regional chemotherapy and intralesional therapies for patients with in-transit melanoma metastases. Ann Surg Oncol 27,35 – 43 (2020).

https://doi.org/10.1245/s10434-019-07760-7

C.V. Angeles, MD, S. L. Wong, MD and G. Karakousis, MD

Between 1980-2004 there have been six randomized controlled trials (RCTs) performed to evaluate the width of surgical margin excision for primary cutaneous melanoma and its influence on recurrence and survival. These RTCs, related current recommendations and long-term follow-up data, as well as a contemporary, actively enrolling trial are summarized and discussed in this Landmark Series. Ann Surg Oncol 27, 3 – 12 (2020).

https://doi.org/10.1245/s10434-019-07866-y

Alexander C. J. van Akkooi, MD, PhD and Andrew J. Spillane, MD

Historically, patients with stage III melanoma had, on average, a poor prognosis, with 5-year overall survival (OS) rates dropping to 32% for stage IIID patients, even after the intention to perform curative surgery;1 however, this was before the advent of effective systemic therapy options for melanoma patients in any stage. First advances were the introduction of immune checkpoint blockade (ICB) with anti-CTLA-4 or BRAF inhibition in BRAF-mutated, stage IV melanoma patients. Later, ICB with anti-PD-1 or combination ipilimumab/nivolumab and combined BRAF/MEK inhibition spurred on these advances. Finally, in recent history, adjuvant systemic therapy for resected stage III melanoma proved safe and effective, leading to approvals by the US FDA, European Medicines Agency (EMA), and the Therapeutic Goods Administration (TGA). Until the advent of effective systemic therapy for melanoma, there was virtually no possibility for an effective approach with neoadjuvant systemic therapy (NAST).

https://link.springer.com/article/10.1245/s10434-020-08570-y

C.V. Angeles, MD, S.L. Wong, MD, MS, and G. Karakousis, MD

Between 1980 and 2004, six randomized, controlled trials (RCTs) have been performed to evaluate the width of surgical margin excision for primary cutaneous melanoma and its influence on recurrence and survival. These trials have led to the current recommendation of not more than a 2-cm margin excision and have allowed reduced morbidity of surgery for primary melanoma. Long-term follow-up data has been published which has led to impactful knowledge of the natural history of this disease, yet controversy remains for 1- to 2-mm thickness melanomas. Interpretation of these trials must be done in light of them enrolling patients before the use of sentinel node biopsy and contemporary immunotherapy regimens. These RCTs as well as a contemporary, actively enrolling trial are summarized and discussed in this review.

https://link.springer.com/article/10.1245/s10434-019-07866-y

Danielle M. Bello, MD and Mark B. Faries, MD

Management of regional lymph nodes in patients with melanoma has evolved significantly in recent years. The value of nodal intervention, long utilized for its perceived therapeutic benefit, has now shifted to that of a critical prognostic procedure used to guide clinical decision making. This review focuses on the three landmark, randomized controlled trials evaluating the role of surgery for regional lymph nodes in melanoma: Multicenter Selective Lymphadenectomy Trial I (MSLT-I), German Dermatologic Cooperative Oncology Group-Selective Lymphadenectomy Trial (DeCOG-SLT), and Multicenter Selective Lymphadenectomy Trial II (MSLT-II).

https://link.springer.com/article/10.1245/s10434-019-07830-w

Michael E. Egger, MD, MPH, Charles W. Kimbrough, MD, Arnold J. Stromberg, PhD, Amy R. Quillo, MD, Robert C.G. Martin II, MD, PhD, Charles R. Scoggins, MD, MBA; and Kelly M. McMasters, MD, PhD

Quality of life (QOL) and physical condition (PC) outcomes after sentinel lymph node biopsy (SLNB), completion lymph node dissection (CLND), and adjuvant therapy with interferon alfa-2b (IFN) were evaluated in this study.

https://link.springer.com/article/10.1245/s10434-015-5074-2

Georgia M. Beasley, MD, Jonathan S. Zager, MD, and John F. Thompson, MD

In-transit melanoma represents a distinct disease pattern in which melanoma recurs as dermal or subcutaneous nodules between the primary melanoma site and the draining regional lymph node basin. The disease pattern is often not amenable to complete surgical resection. Since the 1950s, regional therapies have been explored for the treatment of this disease entity, with the goal of maximizing delivery of the therapeutic agent to the tumor while minimizing systemic toxicity. We reviewed landmark studies describing and evaluating regional chemotherapy and intralesional therapies for patients with in-transit melanoma metastases.

https://link.springer.com/article/10.1245%2Fs10434-019-07760-7

Neuroendocrine

Catherine G. Tran, MD, Scott K. Sherrman MD, and James R. Howe, MD

Surgical resection is the foundation for treatment of small bowel neuroendocrine tumors (SBNETs). Guidelines for surgical management of SBNETs rely on retrospective data, which suggest that primary tumor resection and cytoreduction improve symptoms, prevent future complications, and lengthen survival. In advanced NETs, improvement in progression-free survival has been reported in large, randomized, controlled trials of various medical treatments, including somatostatin analogues, targeted therapy, and peptide receptor radionuclide therapy. This review discusses important studies influencing the management of SBNETs and the limitations of current evidence regarding surgical interventions for SBNETs.

https://link.springer.com/article/10.1245/s10434-020-09566-4

Sarcoma Cancer

Multimodality treatment of primary soft tissue sarcoma has evolved over the last 50 years, including seminal studies in amputation versus limb-sparing surgery, incorporation of radiation therapy (XRT), and the continuing controversy over the utilization and efficacy of systemic chemotherapy. We review the landmark studies in the multimodality management of primary extremity and trunk soft tissue sarcoma.

Christina L. Roland, MD, MS, Winan van Houdt, MD and Alessandro Gronchi, MD

https://doi.org/10.1245/s10434-020-08872-1

Emily Z. Keung MD, Chandrajit P. Raut MD and Piotr Rutkowski MD, PhD

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Complete resection is the only potentially curative treatment, although recurrence is common, occurring in approximately 40–50% of patients. The introduction of effective molecularly targeted therapies for GISTs has dramatically changed the clinical management paradigms for, and prognosis of, patients with intermediate- and high-risk GISTs, as well as those with locally advanced and metastatic disease. In this article, we review landmark studies that evaluated the use and efficacy of the tyrosine kinase inhibitors imatinib and sunitinib in the adjuvant and neoadjuvant settings for resectable primary and limited resectable metastatic GISTs.

https://doi.org/10.1245/s10434-020-08869-w

Thoracic Cancer

Taylor Kantor MD and Elliot Wakeam MD, MPH

The treatment of mesothelioma has evolved slowly over the last 20 years. While surgery as a standalone treatment has fallen out of favor, the importance of multimodality treatment consisting of combinations of chemotherapy, radiotherapy, and surgery have become more common in operable, fit patients. In this review, we discuss trials in surgery, chemotherapy, and radiation that have shaped contemporary multimodality treatment of this difficult malignancy, and we touch on the new and emerging immunotherapeutic and targeted agents that may change the future treatment of this disease. We also review the multimodality treatment regimens, with particular attention to trimodality therapy and neoadjuvant hemithoracic radiation strategies.

Landmark Trials in the Surgical Management of Mesothelioma

The treatment of mesothelioma has evolved slowly over the last 20 years. While surgery as a standalone treatment has fallen out of favor, the importance of multimodality treatment consisting of combinations of chemotherapy, radiotherapy, and surgery have become more common in operable, fit patients.

Marcus E. Eby, MD and Christopher W. Seder, MD

Management of stage 3A non-small cell lung cancer (NSCLC) has evolved significantly during the last several decades. Despite this, a universally accepted algorithm to guide clinical decision-making remains elusive. The controversy surrounding the management of stage 3A NSCLC stems primarily from the innate heterogeneity of the disease and the varied results observed with treatment.

Early studies established that surgery alone yields poor survival rates for patients with NSCLC and ipsilateral mediastinal lymph node involvement, likely due to the presence of residual mediastinal disease after resection.1 Subsequent randomized trials aimed at improving locoregional control demonstrated that treatment with concurrent chemoradiotherapy (CRT) is superior to both radiation treatment (RT) alone and sequential chemotherapy followed by RT.2,3,–4 However, the ongoing desire to improve locoregional control led to examination of the safety and efficacy of trimodality therapy comprising induction CRT followed by surgical resection.5,6

This review focused on the landmark trials conducted by the Southwest Oncology Group (SWOG) 88057 and the Intergroup (INT) 0138,9 their role in establishing current treatment algorithms using induction CRT, and the potential benefits of surgical resection for selected patients with stage 3A NSCLC.

https://link.springer.com/article/10.1245%2Fs10434-020-08553-z

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