AO Spine Clinical Practice Recommendations: Current Systemic Oncological Treatments with the Largest Impact on Patients with Metastatic Spinal Disease

Abstract

Study Design

Literature review with clinical recommendation.

Objective

To provide the readers with a concise curation of the latest literature in recent advances in systemic oncological therapies and their implications for decision-making in patients with metastatic spinal disease. This review aims to enhance spine specialist’s understanding of modern oncological treatments to facilitate optimal timing and planning of local interventions.

Methods

The latest literature in the topic of advances in oncology was reviewed by a multidisciplinary group of experts in metastatic spinal disease and clinical recommendations were formulated. The recommendations were dichotomously graded into strong and conditional (weak) based on the integration of scientific methodology and content expert opinion. This opinion considered experience and practical issues such as risks, burdens, costs, patient values, and circumstances.

Results

Four high-impact studies were reviewed, demonstrating significant advancements in systemic treatments for metastatic cancers commonly affecting the spine. These studies showed improved survival outcomes and efficacy across breast cancer, colorectal cancer, prostate cancer, and renal cell carcinoma. The findings have important implications for surgical/radiotherapy planning, including considerations for timing of interventions, wound healing, and the potential for extended survival affecting construct durability requirements.

Conclusions

Recent advances in systemic oncological treatments have important implications for managing metastatic spinal disease. Understanding these developments is crucial for spine specialists to optimize decision-making through a multidisciplinary approach, particularly regarding timing of local interventions, strategy of the surgical approach and reconstruction.

Introduction

Recent years have witnessed remarkable progress in cancer therapeutics, with novel agents and combination approaches demonstrating unprecedented efficacy in metastatic disease. The evolving landscape of systemic oncological treatments has direct implications for decision-making in spinal metastases. Modern targeted therapies and immunotherapies can affect surgical wound healing, bleeding risk, and timing of interventions including radiotherapy.^1-4 Additionally, improved survival outcomes with these treatments may influence decisions about construct durability and the extent of surgical intervention. Understanding these interactions is crucial for spine surgeons and radiation oncologists working within multidisciplinary teams.

The AO Spine Knowledge Forum Tumor (AOSKFT), a multidisciplinary international expert group dedicated to improving outcomes in spinal oncology, recognizes the need to bridge the gap between cutting-edge oncological research and spine care. Informing the spine community about the key developments in medical oncology should lead to more effective multidisciplinary care for patients with metastatic spinal disease.

This review aims to bridge the knowledge gap between cutting-edge oncological treatment and spine surgery practice. By focusing on key clinical trials across multiple cancer types, we seek to provide spine specialists with crucial insights about modern systemic treatments that inform surgical decision making. While the selection and administration of systemic treatments remain within the oncologists' domain, spine surgeons and radiation oncologists must understand these treatments' implications for treatment planning and post-operative care.

An independent group of medical oncologists from a tertiary academic hospital was invited to provide a list of landmark publications with particular relevance to clinicians treating patients with metastatic spinal disease. The expert panel from AOSKFT subsequently selected and reviewed publications addressing systemic treatments in breast cancer, prostate cancer, renal cell carcinoma and colorectal cancer – malignancies that frequently metastasize to the spine. A comprehensive analysis of the clinical rationale, study design, key findings, and methodological quality was provided for each selected study. Moreover, we offer evidence-based recommendations for clinical practice, utilizing the GRADE system to assess the strength of recommendations and quality of evidence. ⁵

Recommendations were dichotomously graded into strong and conditional, based on the integration of scientific methodology and content expert opinion. This opinion considered experience and practical issues such as risks, burdens, costs, patient values, and circumstances.

By synthesizing this information, we aimed to equip spine specialists with the knowledge to make informed decisions, facilitate multidisciplinary collaborations, and ultimately enhance the care of patients with metastatic spinal disease. Spinal surgery, radiation treatment and systemic treatments can affect each other, thus we will highlight relevant interactions. This review aims to increase awareness among spine specialists about established systemic therapies that impact the care of patients with metastatic spine disease.

Article 1

DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan vs Trastuzumab Emtansine for Breast Cancer. Cortés J et al. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022. ⁶

Clinical Rationale

For spine surgeons treating patients with HER2-positive breast cancer metastases, this pivotal trial comparing trastuzumab deruxtecan to the standard trastuzumab emtansine is significant. The superior survival outcomes with trastuzumab deruxtecan may influence surgical decision-making regarding construct longevity and the aggressiveness of surgical intervention. Understanding these new therapeutic options helps optimize surgical timing and anticipate potential complications in the context of systemic therapy.

Study Summary

This phase 3, multicenter, open-label, randomized trial compared trastuzumab deruxtecan and trastuzumab emtansine in 524 patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. Trastuzumab deruxtecan showed significant benefits in progression-free survival rate at 12 months (mo.) (75.8% vs 34.1%, P < 0.001), 12-mo overall survival rate (94.1% vs 85.9%), and overall response rate (79.7% vs 34.2%). Subgroup analyses consistently favored trastuzumab deruxtecan and showed a beneficial effect in patients with brain metastases. While adverse events were more frequent with trastuzumab deruxtecan (45.1% vs 39.8% for grade 3 or 4) and 8.2% of patients receiving trastuzumab deruxtecan discontinued treatment due to interstitial lung disease or pneumonitis, rates of interstitial lung disease and pneumonitis were lower than in previous trials.

Methodological Review

This well-conducted multicenter randomized controlled trial was registered with clinicaltrials.gov and adhered to ethical and good clinical practice guidelines. Results were clearly presented, demonstrating trastuzumab deruxtecan’s superiority. Limitations include potential generalizability issues due to patient demographics. The patient population was predominantly Asian (58%–62%) and from Asia (57%–61%), with minimal representation from North America (6.5%) and of White patients (27%). In this trial specific bone or spine metastasis data were not reported. The evidence quality is high (GRADE) given the robust phase 3 randomized controlled trial design with 524 patients, strong statistical significance, comprehensive safety monitoring including independent adjudication, and transparent reporting of outcomes.

Recommendation for Integrating Into Your Clinical Practice

This high-quality study merits strong recommendation for spine surgeons to be aware that trastuzumab deruxtecan therapy significantly improves progression-free survival in patients with HER2-positive metastatic breast cancer. Key surgical considerations include: need for more durable constructs, careful platelet monitoring (thrombocytopenia in 24.9% of patients), preoperative pulmonary assessment (ILD risk 10.5%), and coordination of appropriate drug washout periods, though the therapy has shown manageable adverse event profiles from a surgical perspective.

Article 2

Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. Prager GW et al. New England Journal of Medicine. 2023 May 4;388:1657-67. ⁷

Clinical Rationale

This study evaluated the combination of FTD-TPI (an oral chemotherapeutic) with bevacizumab vs FTD-TPI alone in refractory disease. The findings are relevant for spine surgeons as bevacizumab can impact wound healing and surgical timing, and improved survival with these agents may influence decisions about construct durability and extent of surgical intervention.

Study Summary

This randomized controlled trial included 492 patients with refractory metastatic colorectal cancer, comparing FTD-TPI plus bevacizumab to FTD-TPI alone. At median follow-up of approximately 14 mo., the combination therapy showed superior outcomes with median overall survival of 10.8 mo. versus 7.5 mo. (HR for death: 0.61, P < 0.001). The 12-mo overall and progression-free survival rates were also higher in the combination group. Grade 3 or greater adverse events were similar between groups (72.4% vs 69.5%), with the combination group experiencing higher rates of hypertension, nausea, and neutropenia.

Methodological Review

This study was a randomized controlled prospective study that was performed internationally. The primary endpoint was overall survival. Secondary endpoints were progression-free survival and toxicity. Patients were randomized evenly between arms. Randomization was stratified according to geographic region (North America, European Union or rest of world), time since development of first metastasis (<18 mo. or ≥18 mo.), and RAS status (wild type or mutated). Even though the study reports the number of metastatic sites, specific bone or spine metastasis data were not reported.

The evidence quality is high (GRADE) given the large (492 patients) phase 3 randomized controlled trial design, robust statistical significance, clear eligibility criteria, appropriate stratification factors, comprehensive safety monitoring, and transparent reporting of patient characteristics and outcomes.

Recommendation for Integrating Into Your Clinical Practice

We believe that this study warrants strong recommendation for spine surgeons to recognize that trifluridine-tipiracil and bevacizumab therapy achieves median overall survival of 10.8 mo. even in refractory metastatic colorectal cancer. Key surgical considerations include: when possible washout periods (4-6 weeks pre- and post-surgery) are advised, increased risk of wound breakdown and infection due to frequent neutropenia and thrombocytopenia – consider early involvement of plastic surgery, relatively frequent occurrence of therapy induced anemia and hypertension.

Article 3

Abiraterone plus Prednisone added to androgen deprivation therapy and Docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Fizazi et al. Lancet. 2022 Apr 30;399(10 336):1695-1707. doi: 10.1016/S0140-6736(22)00 367-1. ⁸

Clinical Rationale

For spine surgeons treating metastatic prostate cancer patients, this landmark PEACE-1 trial is particularly relevant as it demonstrated significantly improved survival (median 5.7 years) with triple therapy (ADT, docetaxel, and abiraterone) compared to previous standards. These improved survival outcomes directly impact surgical decision-making regarding construct durability and the aggressiveness of surgical intervention, particularly in patients with de novo metastatic disease.

Study Summary

The PEACE-1 trial, a multicenter, open-label, randomized phase 3 study with a 2 × 2 factorial design, enrolled 1173 men with de novo metastatic prostate cancer. It evaluated the addition of abiraterone plus prednisone, with or without radiotherapy, to standard of care (SOC, ADT plus docetaxel). After median follow-up of 3.5 years for radiographic progression-free survival (rPFS) and 4.4 years for overall survival (OS), adding abiraterone to SOC significantly improved outcomes. rPFS increased from 2.2 to 4.5 years (46% risk reduction), and median OS improved from 4.72 to 5.72 years (18% risk reduction, P = 0.030) with only a modest increase in toxicity. Benefits were consistent across subgroups, with pronounced effects in high-volume disease patients. Approximately 81% of patients had bone metastases although there is no specific subgroup analysis comparing outcomes between patients with and without bone metastases.

Methodological Review

PEACE-1 is the first trial demonstrating that triple systemic therapy (ADT, docetaxel, and abiraterone with prednisone) improves both rPFS and OS in de novo metastatic castration-sensitive prostate cancer without excessive toxicity increase. The study provides mature data for high-volume disease, showing clear improvements when abiraterone is added to ADT with docetaxel. The open-label design is a limitation. The evidence quality is high (GRADE) given the well-designed phase 3 randomized controlled trial with 1173 patients, appropriate stratification factors, clearly defined endpoints, comprehensive subgroup analyses, robust statistical methodology accounting for multiple testing, long follow-up (median 4.4 years), and transparent reporting of both benefits and toxicities.

Recommendation for Integrating Into Your Clinical Practice

Based on this high-quality evidence we propose a strong recommendation for spine surgeons to recognize that recent advances in systemic therapy of patients with metastatic prostate cancer extend progression-free survival and overall survival beyond 5 years. Key surgical considerations include: necessity for durable constructs balanced with bone quality considerations, when possible timing with docetaxel cycles and abiraterone washout periods, moderately frequent neutropenia, hypertension and abnormal liver function, possible negative effects of ADT on wound healing and bone density.

Article 4

Nivolumab plus Cabozantinib vs Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri TK et al. N Engl J Med. 2021 Mar 4;384(9):829-841. doi: 10.1056/NEJMoa2026982. ⁹

Clinical Rationale

For spine surgeons managing renal cell carcinoma metastases, this pivotal trial comparing nivolumab plus cabozantinib vs sunitinib is significant. The combination therapy doubled progression-free survival while maintaining quality of life, which impacts surgical planning and timing. Additionally, understanding these immunotherapy combinations is crucial as they may affect wound healing and show increased efficacy in cases with bone metastases.

Study Summary

The study enrolled 651 adult patients with previously untreated metastatic renal cell carcinoma with a clear cell component, including 24.1% and 22.0% of patients have bone lesions as the most common site of metastases (cabozantinib and nivolumab vs sunitinib, respectively). Patients were randomized to the combination of two active approved agents (cabozantinib and nivolumab) to a single agent active control, another approved agent, sunitinib. The results were clinically and statistically significant at a median follow-up of 18.1 mo. The median PFS for the combination treatment was doubled at 16.6 mo. compared to 8.3 mo. The Hazard Ratio (HR) for progression or death was 0.51, with a P < 0.001. The time to response and duration of response were also superior for the doublet. As expected, the ≥ grade 3 toxicities were higher for the doublet. The Quality of Life (QoL) was preserved over time in the doublet compared to a steady decline in the Sunitinib arm. Notably, the combination showed superior efficacy in patients with bone metastases compared to those without (HR 0.34 vs 0.57 for progression-free survival), suggesting particular benefit in this population.

Methodological Review

The study was a well-designed prospective randomized trial with appropriate stratification for known prognostic factors included in the International Metastatic RCC Database Consortium (IMDC) risk scores. Sample size was calculated based on overall two-sided alpha of 0.05 for the primary endpoint of PFS and hierarchical testing was used to assess secondary endpoints of OS and RR. This study provides high quality of evidence (GRADE).

Recommendation for Integrating Into Your Clinical Practice

This study warrants strong recommendation for spine surgeons to recognize that combination therapy with nivolumab plus cabozantinib in advanced renal cell carcinoma doubles progression-free survival and shows superior efficacy in patients with bone metastases. Key surgical considerations include: high local response rate may allow less aggressive debulking of the tumor, frequent therapy induced diarrhea, hypertension and liver abnormalities, no negative impact on wound healing observed.

Discussion

Evolving Landscape of Systemic Oncological Treatments

The reviewed studies demonstrate unprecedented improvements in survival across multiple cancers that commonly metastasize to the spine. These advances are fundamentally changing the decision-making landscape for spine specialists. With survival reaching nearly 6 years for prostate cancer with triple therapy, and dramatic improvements in other cancers, we must adapt our palliative interventions to account for this extended survival timeline.

The implications for spine surgeons and radiation oncologists extend far beyond simply knowing about new systemic therapies.^10-12 These advances necessitate careful consideration of construct durability, surgical timing and radiotherapy, wound healing protocols, and complication management strategies.

Each therapeutic class presents distinct surgical considerations. Targeted therapies require specific washout periods and wound healing monitoring. Novel antibody-drug conjugates need careful toxicity management. While bone-specific outcomes remain underreported in most trials, some show promising results, particularly nivolumab/cabozantinib in RCC bone metastases ⁹ This may have impact on the timing and extent of the intervention.

The era of modern systemic therapies demands that spine specialists evolve from being purely technical experts to becoming sophisticated multidisciplinary clinicians who can optimize surgical care within complex treatment protocols.

Summary of Methodological Quality

The reviewed studies represent high-quality evidence for informing spine surgeons' and radiation oncologists’ decision-making, with four large phase 3 randomized controlled trials demonstrating robust survival improvements that directly impact the timing and aggressiveness of local interventions for metastatic disease. The trials were particularly relevant as they included patients with bone metastases and maintained balanced baseline characteristics between arms, with comprehensive subgroup analyses and thorough reporting of the adverse events. Importantly for treatment planning, the studies rigorously documented not just survival but also quality of life metrics and timing of disease progression, providing reliable data to guide construct durability decisions and estimate postoperative recovery timelines.

Content Summary

Several key themes emerged from our review that significantly impact spine surgery practice. Most striking are the unprecedented survival improvements: prostate cancer extending to 5.72 years with triple therapy, ⁸ and HER2-positive breast cancer showing 75.8% progression-free survival at one year. ⁶ Even traditionally challenging cancers demonstrate meaningful gains, with doubled progression-free survival in renal cell carcinoma ⁹ and improved survival in refractory colorectal cancer. ⁷

Each therapeutic class presents distinct considerations especially for surgical cases. Targeted therapies require specific washout periods and wound healing monitoring. Immunotherapies offer durable responses but complicate perioperative steroid use. Novel antibody-drug conjugates need careful toxicity management. While bone-specific outcomes remain underreported in most trials, some show promising results, particularly nivolumab/cabozantinib in RCC bone metastases. ⁹

Practice Recommendations

Modern cancer therapies have dramatically improved survival rates, influencing decision-making in several ways. Construct planning should balance durability for longer survival with minimal tissue disruption to allow prompt systemic therapy resumption. Minimally invasive techniques may offer advantages in appropriate cases.

Surgical timing requires careful coordination with oncology teams, considering specific washout periods for different agents (4-6 weeks for antiangiogenic agents, variable for immunotherapy). Enhanced wound healing monitoring is essential, particularly with agents affecting angiogenesis or immune responses. Early plastic surgery involvement should be considered for high-risk cases.

A multidisciplinary approach through regular tumor board participation ensures optimal intervention timing and appropriate therapy modifications.

The data support:

• (1) Multidisciplinary Integration: combined decisions on surgical timing, construct planning, and systemic therapy coordination

• (2) Therapeutic Knowledge: understanding of extended survival and therapy-specific complications

• (3) Treatment Planning: construct durability and surgical timing based on drug-specific requirements and treatment windows

• (4) Personalized Approach: balance of tumor response, wound healing considerations, and systemic therapy needs

• (5) Risk Assessment Update: integration of improved survival data and therapy-specific complications into decision algorithms

This reflects the shift from palliative to long-term management demonstrated by current trials.

ORCID iDs

Marcin Czyz https://orcid.org/0000-0001-7224-4272

Joost Rutges https://orcid.org/0000-0002-9452-415X

Jiong Hao Jonathan Tan https://orcid.org/0000-0002-9237-2586

Cordula Netzer https://orcid.org/0000-0001-7381-373X

Laurence D. Rhines https://orcid.org/0000-0002-8474-1521