Surgical oncology for the general surgeon

Despite the recent move to board certification in complex surgical oncology, general surgeons still perform most cancer operations in the U.S., particularly for the more common tumors of the breast, skin, and lower gastrointestinal tract. Surgical oncology has increasingly become more multidisciplinary, with the incorporation of molecular profiling, targeted therapy, and neoadjuvant and adjuvant therapy protocols.

The purpose of this review is to update surgeons on the latest advances in our understanding of tumor biology as it pertains to the surgical care of cancer patients. In addition, the proper sequencing of therapy and findings of the latest cancer clinical trials are discussed from the perspective of the surgical oncologist.

Melanoma

Significant changes in the surgical and medical management of melanoma have occurred in the last decade, supporting the need for multidisciplinary management. Early, localized disease is still treated definitively with surgery, while the sentinel lymph node biopsy (SLNB) procedure is used for pathologic staging of intermediate or high-risk melanoma.¹ The Multicenter Selective Lymphadenectomy Trial II (MSLT-II) supported an active surveillance and salvage surgery strategy for appropriate SLNB-positive patients (see Figure 1).²

FIGURE 1. MSLT II TRIAL PRIMARY ENDPOINT OF MELANOMA-SPECIFIC SURVIVAL

Concurrently, targeted therapies and immunotherapies transitioned from use in stage IV disease to utilization in the stage III and resected stage IV adjuvant setting.³ We are still learning how to balance risk/benefit in these patients. Ongoing trials are focused on the neoadjuvant management of high-risk stage III melanoma, with anticipated changes in medical and surgical management of disease based upon pathologic response, although this approach is not standard of care. Throughout the field, efforts continue to optimize patient-specific management as we integrate surgery and systemic therapy for complex melanoma patients.

Breast cancer

As cancer treatment continues to become more individualized, there has been increasing interest in de-escalating breast cancer therapy. Goals of de-escalation include minimizing interventions and reducing side effects and toxicities while preserving or even improving outcomes. Neoadjuvant chemotherapy traditionally has been employed to downstage large or inoperable tumors to allow for breast conservation therapy. However, indications for neoadjuvant therapy are expanding, and genomic assays can be used to identify additional breast cancer patients who might be appropriate candidates.⁴ These genomic assays also can guide providers in determining whether chemotherapy or endocrine treatment would be a preferred approach when planning a neoadjuvant protocol.

Limited but emerging data indicate that these assays may be predictive for pathologic complete response to neoadjuvant therapy in both the breast and axilla. While de-escalation of breast cancer surgery is well-established for local therapy of the breast, more recently, attention has turned toward downstaging the clinically node-positive axilla with neoadjuvant therapy. Achieving a complete pathologic response in the axilla may allow one to omit an axillary dissection and avoid its associated chronic side effects, such as lymphedema.

TABLE 1. SUMMARY OF STUDIES OF SENTINEL LYMPH NODE BIOPSY FOLLOWING NEOADJUVANT THERAPY IN

CLINICALLY NODE-POSITIVE PATIENTS WITH BREAST CANCER

Several studies have shown that sentinel node biopsy after neoadjuvant therapy can be safely performed with acceptably low false-negative rates (see Table 1).⁵ Placing a clip in the known clinically positive node and excising it along with the sentinel nodes (that is, targeted axillary dissection) further lowers the false-negative rate.⁶ Two ongoing prospective clinical trials, Alliance 11202 and NSABP-B51/RTOG 1304, are further evaluating the surgical and radiation management of the axilla in node-positive breast cancer after neoadjuvant therapy. When planning a strategy of de-escalating breast cancer treatment with neoadjuvant therapy, a multidisciplinary team approach that includes medical oncology and radiation oncology is beneficial given the complexity of care coordination.

Colorectal cancer

Several recent clinical trial findings have advanced our knowledge of patient care for patients with colon cancer. The FOxTROT (Fluorouracil and Oxaliplatin With or Without Panitumumab In Treating Patients With High-Risk Colon Cancer That Can Be Removed by Surgery) study compared the efficacy of six weeks of FOLFOX before resection followed by 18 weeks of FOLFOX with adjuvant chemotherapy alone in patients with operable, non-obstructive colon cancer (see Figure 2). This study did not reach statistical significance in the primary endpoint of recurrence-free survival but did reveal an increased pathologic response and reduced incomplete resections in the neoadjuvant arm.⁷ We are waiting for the final trial results to be published.

Treatment of stage IV patients with microsatellite-instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors also has changed dramatically based on the KEYNOTE-177 trial, which demonstrated improved progression-free survival in patients treated with a combination of pembrolizumab and chemotherapy compared with chemotherapy alone (48 percent and 19 percent at two years, respectively).⁸ This landmark study has changed the standard of care for this group of patients.

FIGURE 2. FOxTROT TRIAL DESIGN SCHEMA: COLON CANCER

For patients with RAS-wildtype tumors, the recently published EPOC study yielded some surprising results. The addition of an anti-EGFR antibody to perioperative chemotherapy in patients with operable colorectal liver metastases showed detrimental oncologic outcomes and was closed to recruitment.⁹

Lastly, there is growing interest in the use of circulating tumor DNA (ctDNA) to facilitate early detection of minimal residual disease in patients at highest risk for colon cancer recurrence. In one study, ctDNA detection allowed for detection of recurrence approximately eight months before radiographic detection and outperformed carcinoembryonic antigen (CEA) as a biomarker for disease relapse.¹⁰ Although we are still in the process of determining how to best use ctDNA to guide therapy, several clinical trials, such as IMPROVE-IT (Intervention Trial Implementing Non-Invasive Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients with Colorectal Cancer) and COBRA (Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIA Colon Cancer After Surgery), will help clarify and validate its use as a predictor of response.

Summary

Surgical oncology for common tumor sites has evolved significantly through an expansion of clinical trials. Adherence to the new standards of cancer surgery and treatment should be embedded into clinical practice for the continued benefit of our patients.

References

1. Wong SL, Faries MB, Kennedy EB, et al. Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update. Ann Surg Oncol. 2018;25(2):356-377.
2. Faries MB, Thompson JF, Cochran AJ, et al. Completion dissection or observation for sentinel-mode metastasis in melanoma. N Engl J Med. 2017;376(23):2211-2222.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824-1835.
4. Pease A, Riba L, Gruner R, et al. Oncotype DX Recurrence Score as a predictor of response to neoadjuvant chemotherapy. Ann Surg Oncol. 2019;26(2):366-371.
5. Caudle A, Bedrosian I, Milton D, et al. Use of sentinel lymph node dissection after neoadjuvant chemotherapy in patients with node-positive breast cancer at diagnosis: Practice patterns of American Society of Breast Surgeons members. Ann Surg Oncol. 2017;24(10):2925-2934.
6. Caudle A, Yang W, Krishnamurthy S, et al. Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: Implementation of targeted axillary dissection. J Clin Oncol. 2016;34(10):1072-1078.
7. Seymour MT, Morton D. FOxTROT: An international randomised controlled trial in 1052 patients (pts) evaluating neoadjuvant chemotherapy (NAC) for colon cancer. J Clin Oncol. 2019;37(15_suppl):3504.
8. André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207-2218.
9. Bridgewater JA, Pugh SA, Maishman T, et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): Long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21(3):398-411.
10. Henriksen TV, Tarazona N, Reinert T, et al. Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients. J Clin Oncol. 2021;39(3_suppl):11.