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Neoadjuvant therapy
Neoadjuvant therapy
Neoadjuvant therapy
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Neoadjuvant therapy
MeSHD020360

Neoadjuvant therapy is the administration of therapeutic agents before a main treatment. One example is neoadjuvant hormone therapy prior to radical radiotherapy for adenocarcinoma of the prostate. Neoadjuvant therapy aims to reduce the size or extent of the cancer before using radical treatment intervention, thus both making procedures easier and more likely to succeed and reducing the consequences of a more extensive treatment technique, which would be required if the tumor were not reduced in size or extent.

Another related concept is that neoadjuvant therapy acts on micrometastatic disease. The downstaging is then a surrogate marker of efficacy on undetected dissemination, resulting in improved longtime survival compared to the surgery-alone strategy. [citation needed]

This systemic therapy (chemotherapy, immunotherapy or hormone therapy) or radiation therapy is commonly used in cancers that are locally advanced, and clinicians plan an operation at a later stage, such as pancreatic cancer. The use of such therapy can effectively reduce the difficulty and morbidity of more extensive procedures.

The use of therapy can turn a tumor from untreatable to treatable by shrinking the volume. Often, it is unclear which surrounding structures are directly involved in the disease and which are just showing signs of inflammation. By administering therapy, a distinction can often be made. Some doctors give the therapy in the hope that a response is seen, and they can then decide what is the best course of action. In some cases, magnetic resonance imaging can predict the response of a patient to neoadjuvant therapy, for example in ovarian cancer.[1]

Not everyone is suitable for neoadjuvant therapy because it can be extremely toxic. Some patients react so severely that further treatments, especially surgery, are precluded, and the patient is rendered unfit for anesthetic.[2]

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Neoadjuvant therapy

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Neoadjuvant therapy is a administered before the primary intervention, most commonly , to reduce tumor size, facilitate resection, and potentially enhance overall outcomes by addressing micrometastases early. Originally conceptualized as delivered prior to local treatments like , the approach has evolved to incorporate and other modalities before surgical procedures. Common types include , , , , and combinations such as chemoradiation, tailored to the cancer's characteristics. This therapy is particularly utilized for solid tumors in cancers like , colorectal, , , and rectal malignancies, where preoperative administration can downstage the disease over a period ranging from weeks to a year, followed by within about a month of completion. Key benefits encompass shrinking tumors to enable less invasive surgeries—for instance, converting a to a in —eliminating the need for surgery in select cases, lowering recurrence risks by targeting subclinical spread, and allowing clinicians to gauge treatment responsiveness through pathological assessment post-therapy. Clinical evidence supports its efficacy, with studies demonstrating equivalent or superior survival rates compared to postoperative (adjuvant) approaches in certain settings, such as neoadjuvant for yielding outcomes on par with adjuvant regimens. However, it carries risks including treatment-specific side effects like , , and susceptibility, which are managed through supportive care. The choice of neoadjuvant therapy depends on factors including cancer stage, type, patient health, and tumor biology, with ongoing research exploring its integration with novel immunotherapies to further optimize results.

Definition and Background

Definition

Neoadjuvant therapy refers to the administration of therapeutic agents, such as drugs or , prior to the primary treatment modality, most commonly , aimed at reducing tumor size, eradicating micrometastases, or enhancing overall treatment tolerance. This approach, also known as preoperative or primary , allows for the delivery of systemic treatments in patients with operable disease to diminish the local and regional tumor burden before definitive local intervention. Common examples include neoadjuvant , , targeted therapies, or preceding surgical resection, though it may occasionally precede as the primary treatment. The core purposes of neoadjuvant therapy encompass tumor downstaging to facilitate improved resectability, providing an assessment of tumor sensitivity to specific therapeutic agents, and converting initially unresectable tumors into resectable ones. By shrinking the , it enhances the feasibility of complete surgical removal and addresses subclinical through early systemic exposure. Additionally, it can reduce the risk of recurrence by targeting micrometastases that might otherwise lead to distant spread. In general, neoadjuvant therapy is applied in cases of locally advanced or operable cancers where preoperative systemic control is essential to optimize outcomes, distinguishing it from administered post-primary treatment or from palliative approaches used in metastatic settings focused on symptom relief rather than curative intent. This strategy was first notably employed in breast and rectal cancers to address inoperable locally advanced disease.

Historical Development

The concept of neoadjuvant therapy emerged in the 1970s, primarily as neoadjuvant chemotherapy for locally advanced, unresectable , aiming to shrink tumors and enable surgical resection. Early trials, such as those conducted by the group, demonstrated the feasibility of this approach in improving operability without compromising survival, marking a shift from postoperative adjuvant strategies. By the , neoadjuvant therapy expanded to rectal cancer, with preoperative radiotherapy introduced to reduce local recurrence rates following surgery. Pivotal studies, including the Swedish Rectal Cancer Trial initiated in 1987, established short-course radiotherapy as a standard to enhance local control, influencing global treatment paradigms despite initial postoperative focus. The 1990s and 2000s saw a transition to multimodal neoadjuvant regimens, incorporating chemoradiotherapy for esophageal and pancreatic cancers to address micrometastatic disease and improve resectability. Concurrently, targeted therapies like trastuzumab for HER2-positive breast cancer were integrated around 2005, boosting pathologic complete response rates in neoadjuvant settings. From the 2010s onward, neoadjuvant immunotherapy gained prominence, exemplified by trials like SWOG S1801 showing improved event-free survival with perioperative pembrolizumab in resectable stage III/IV melanoma. Total neoadjuvant therapy (TNT) for rectal cancer also rose, delivering full chemotherapy and radiotherapy preoperatively to optimize systemic control, as validated in studies like RAPIDO. Historical reviews, such as those in Seminars in Oncology, underscore this evolution from adjuvant-dominant to neoadjuvant paradigms across solid tumors.

Medical Indications

In Oncology

Neoadjuvant therapy is predominantly applied in oncology to treat various solid tumors, particularly those that are locally advanced or borderline resectable, where preoperative treatment aims to reduce tumor burden and facilitate surgical intervention. In breast cancer, it has become a standard approach for locally advanced or inflammatory subtypes, such as triple-negative or HER2-positive disease, to shrink tumors and enable breast-conserving surgery rather than mastectomy. Response to this therapy is commonly evaluated through pathological complete response (pCR), defined as no residual invasive cancer in the breast or lymph nodes at surgery. In rectal cancer, neoadjuvant therapy typically involves preoperative chemoradiotherapy to downsize tumors, preserve function, and lower the risk of local recurrence. The total neoadjuvant therapy (TNT) strategy, which administers the full course of before surgery, has gained prominence to enhance systemic control early in treatment. Applications extend to other key cancers, including , where neoadjuvant approaches improve rates of R0 resection (complete tumor removal with negative margins). For non-small cell at stage III, it serves to downstage tumors and increase resectability. In muscle-invasive , regimens like MVAC are used preoperatively to reduce tumor size before . Neoadjuvant therapy is also employed in borderline resectable with regimens such as to convert inoperable cases to operable ones. For head and neck cancers, it helps preserve organ function by shrinking tumors prior to surgery or radiation. In high-risk stage III , immunotherapy-based neoadjuvant treatment targets nodal disease to improve surgical outcomes. The primary rationale for neoadjuvant therapy in these oncological settings is to address potential micrometastatic disease early, thereby reducing the risk of distant spread, while simultaneously improving resectability rates, such as increasing R0 resection from 69% to 92% in and from 74% to 84% in gastric cancer, depending on the cancer type. Major guidelines from organizations like the (NCCN) and the (ASCO) have recommended its use prominently in breast and rectal cancers since the early , with expansions to indications like in the 2020s based on recent clinical trials. Historical adoption began prominently in breast and rectal cancers, where neoadjuvant strategies were integrated into standard care based on landmark studies demonstrating feasibility and tumor downsizing.

In Non-Oncological Conditions

Neoadjuvant therapy, primarily established as a preoperative treatment to shrink tumors in , finds limited application in non-oncological conditions through analogous preparatory medical interventions aimed at optimizing surgical outcomes. These uses, however, rarely employ the term "neoadjuvant" and are supported by sparse evidence from small studies rather than large randomized trials. In prostate conditions such as (BPH), has been investigated to reduce volume prior to surgical procedures. One early study (n=12) demonstrated that short-term androgen deprivation resulted in an average 29% decrease in prostate size after 12 weeks, potentially easing surgical access, though with limited clinical benefit and reversal of effects post-treatment. Despite exploration since the 1980s, this approach remains non-standard due to mixed results in limited trials and no overall improvement in long-term outcomes, as evidenced by meta-analyses showing insufficient benefits to warrant routine use. For benign or inflammatory diseases, preoperative administration of steroids or immunosuppressants serves a similar preparatory function in severe cases of (IBD) before procedures like , aiming to mitigate inflammation and improve tissue handling during surgery. Low-dose perioperative intravenous steroids, for instance, have been deemed safe and feasible in IBD patients undergoing major , with pilot studies reporting no significant increase in postoperative complications. Although not formally designated as neoadjuvant therapy, these interventions draw from the core concept of pre-surgical medical optimization; however, guidelines emphasize cautious use due to risks like delayed healing and negative impacts on outcomes, and applications are confined to select high-risk cases based on case series rather than definitive trials. In preparation for , such as liver transplant in patients with and , short-term medical therapies like non-selective beta-blockers are employed to stabilize and reduce portal pressure prior to . These agents attenuate the common in end-stage , with observational data indicating improved short-term survival among cirrhotic patients listed for transplantation who receive them preoperatively. The neoadjuvant terminology is uncommon here, and protocols focus on individualized optimization rather than standardized neoadjuvant regimens. Across these contexts, evidence remains constrained to case series, retrospective analyses, and small prospective studies, precluding strong recommendations in major guidelines; for example, the American Urological Association's guidelines for BPH management do not endorse routine preoperative due to inadequate robust data supporting efficacy and safety. This contrasts sharply with , where neoadjuvant approaches are guideline-supported for numerous malignancies based on high-impact trials demonstrating benefits.

Types of Neoadjuvant Therapies

Chemotherapy

Neoadjuvant employs cytotoxic agents that primarily target rapidly dividing cells within the tumor, interfering with and replication to induce and tumor regression. This approach not only reduces tumor burden prior to but also permits assessment of tumor chemosensitivity through serial or post-treatment , guiding subsequent therapeutic decisions. As the first-line neoadjuvant modality, it emerged in the 1970s through pioneering trials for locally advanced , marking a shift from surgery-first strategies to preoperative systemic treatment. Common regimens vary by cancer type but typically involve combination therapies to enhance efficacy while balancing toxicity. For , anthracycline-taxane-based protocols such as AC-T—comprising and followed by —represent a standard, administered sequentially to maximize antitumor activity. In , platinum-based combinations like plus are widely used to downstage muscle-invasive disease before . For , the regimen, which includes , , , and , has shown promise in borderline resectable cases by improving resectability rates. Treatment duration generally spans 3-6 cycles, equivalent to 2-4 months, allowing sufficient time for tumor response without unduly delaying . In the neoadjuvant setting, this modality offers advantages such as higher pathological complete response (pCR) rates in chemosensitive tumors—for instance, 20-40% pCR in —correlating with improved long-term outcomes, and the opportunity for response-based dose adjustments to optimize individual .

Radiotherapy and Chemoradiotherapy

Neoadjuvant radiotherapy employs ionizing radiation to induce DNA damage in tumor cells, primarily through the generation of reactive oxygen species that cause double-strand breaks, leading to cell cycle arrest, apoptosis, or mitotic catastrophe, thereby facilitating tumor shrinkage and sterilization of surgical margins. Administering radiation preoperatively in the neoadjuvant setting minimizes toxicity to adjacent structures like the small bowel, as the tumor volume is larger during postoperative irradiation, increasing the irradiated field and risk of gastrointestinal complications. Common regimens for neoadjuvant radiotherapy in rectal cancer include short-course approaches delivering 25 Gy in 5 fractions over one week, which prioritize rapid downstaging and sphincter preservation, and long-course options providing 50.4 Gy in 28 fractions over 5-6 weeks for more gradual tumor regression. Chemoradiotherapy enhances these effects by combining with concurrent systemic agents such as 5-fluorouracil (5-FU) or oral , which sensitize tumor cells to while addressing micrometastatic disease. This modality is predominantly applied in rectal and s to achieve pathologic downstaging, with T-stage reduction observed in 40-60% of locally advanced rectal cases, enabling R0 resections and improved local control. In , neoadjuvant chemoradiotherapy similarly promotes downstaging in a majority of patients, reducing tumor burden and nodal involvement prior to esophagectomy. These applications briefly reference integration with components to optimize concurrent delivery, ultimately supporting enhanced surgical feasibility such as wider margins and reduced operative morbidity. The total neoadjuvant therapy (TNT) paradigm, established as a standard for locally advanced rectal cancer since the 2010s, sequences full systemic upfront followed by chemoradiotherapy before , aiming to maximize distant control while leveraging for local effects. Seminal evidence from the German CAO/ARO/AIO-94 demonstrated that preoperative chemoradiotherapy significantly improves local control, with 5-year cumulative incidence of local recurrence of 6% compared to 13% with postoperative approaches, without impacting overall survival but establishing neoadjuvant timing as superior for pelvic recurrence prevention.

Targeted and Immunotherapies

Targeted therapies represent a precision approach in the neoadjuvant setting, utilizing agents that inhibit specific molecular drivers of cancer progression, such as receptor tyrosine kinases. In , trastuzumab, a targeting the HER2 receptor, combined with , has substantially improved pathological complete response (pCR) rates from 19% in the control arm to 38% with trastuzumab addition, as demonstrated in the phase III trial involving 235 patients with locally advanced disease. Similarly, in head and neck squamous cell carcinoma, the EGFR inhibitor , when integrated into neoadjuvant regimens with platinum-based , has enhanced tumor response rates, with phase II studies reporting objective response rates exceeding 80% and facilitating organ preservation in select cases. Immunotherapies, particularly immune checkpoint inhibitors targeting the axis, have transformed neoadjuvant treatment by harnessing the patient's against tumors prior to . The phase III KEYNOTE-522 trial in showed that adding to neoadjuvant increased pCR rates to 64.8% (95% CI, 59.9-69.5) compared to 51.2% (95% CI, 44.1-58.3) with placebo plus , with a treatment difference of 13.6 percentage points (P<0.001) across 1,174 patients. Neoadjuvant-adjuvant regimens incorporating PD-1 inhibitors, such as nivolumab or , have also yielded promising results in and non-small cell (NSCLC), where major pathological response (MPR)—defined as ≤10% viable tumor cells—serves as a key endpoint correlating with long-term outcomes. These therapies operate through distinct mechanisms to achieve tumor regression in the neoadjuvant context. Targeted agents like bind extracellularly to HER2, inhibiting receptor dimerization and downstream PI3K/AKT signaling that drives proliferation, while EGFR inhibitors such as prevent ligand binding and receptor activation, leading to halted cell growth and increased susceptibility to . In contrast, immunotherapies like PD-1/ inhibitors block inhibitory signals on T-cells, promoting cytotoxic immune activation, infiltration into the , and durable antitumor responses, often evidenced by MPR in resected specimens. Neoadjuvant protocols typically involve 2-4 cycles of these agents administered before , frequently combined with in high-risk scenarios, a practice that gained FDA approval and became standard for certain indications in the 2020s following pivotal trials. Patient selection remains a critical challenge, relying on biomarkers including HER2 overexpression for targeted therapies, expression levels (e.g., CPS ≥10) for PD-1 inhibitors, and microsatellite instability-high (MSI-H) status to predict responsiveness across tumor types.

Endocrine Therapy

Endocrine therapy, also known as , is utilized in neoadjuvant settings for hormone receptor-positive cancers, particularly -positive (ER+) and , to block hormonal signals that promote tumor growth and thereby reduce tumor size prior to surgery. In , aromatase inhibitors such as or , or selective modulators like , are commonly employed for postmenopausal women with ER+/HER2-negative tumors, achieving clinical response rates of 60-80% and facilitating breast-conserving surgery in operable cases. Protocols typically last 3-6 months, allowing assessment of tumor responsiveness via or Ki-67 proliferation index changes, with pathological complete response rates lower than (around 10-15%) but significant downstaging in responsive tumors. In , neoadjuvant (ADT) using luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgens, or newer agents like abiraterone, is applied for high-risk localized disease to shrink tumors and improve surgical margins, reducing volume by 20-50%. However, while it enhances local control, evidence as of 2025 does not support improved overall survival compared to adjuvant settings, and its routine use before radical is not recommended outside clinical trials per NCCN guidelines. Patient selection focuses on tumor grade, PSA levels, and Gleason score, with ongoing research exploring combinations with novel anti-androgens for better pathologic responses.

Administration and Protocols

Timing and Sequencing

Neoadjuvant therapy is generally initiated as soon as possible after , often within 4-8 weeks, to minimize disease progression while allowing time for comprehensive staging, multidisciplinary , and patient preparation. The completion of neoadjuvant treatment is typically scheduled 4-6 weeks prior to to facilitate recovery from acute toxicities, optimize surgical conditions, and enable assessment of treatment response. For instance, neoadjuvant regimens commonly span 3-6 months, involving multiple cycles to achieve maximal tumor downsizing before proceeding to resection. In terms of sequencing, systemic therapies such as chemotherapy or immunotherapy are usually administered first to address potential micrometastatic disease and systemic spread, followed by local therapies like radiation if indicated for tumor control. Total neoadjuvant therapy (TNT) represents an advanced approach where the full course of intended adjuvant systemic chemotherapy is delivered preoperatively, often integrating chemoradiotherapy to enhance pathological complete response rates without postponing surgery excessively. Intervals between chemotherapy cycles are generally 2-4 weeks, depending on the regimen and patient tolerance, to balance efficacy with recovery from myelosuppression. Following radiation, a 6-8 week interval before surgery is recommended to reduce perioperative complications while allowing maximal tumor regression. Several factors influence the precise timing and sequencing of neoadjuvant therapy, including tumor biology, patient fitness, and early response to treatment. Rapidly proliferating tumors may necessitate expedited to prevent unresectability, whereas slower-growing lesions with favorable responses might justify extended intervals to further enhance downsizing. Patient performance status and comorbidities must be considered to ensure tolerance, potentially adjusting schedules to avoid excessive toxicity. Guidelines from organizations such as the European Society for Medical Oncology (ESMO) and the (NCCN) emphasize these intervals to optimize oncologic outcomes while mitigating risks, with recommendations tailored to specific tumor types but grounded in balancing efficacy, toxicity, and logistical feasibility.

Patient Monitoring and Response Assessment

Patient monitoring during neoadjuvant therapy involves regular evaluations to assess treatment efficacy, detect adverse events early, and guide potential adjustments to the regimen. This includes imaging techniques such as computed tomography (CT) or to measure tumor size changes, blood tests for tumor markers like CA-19-9 in , and toxicity grading using the Common Terminology Criteria for Adverse Events (CTCAE) scale to quantify side effects from grades 1 (mild) to 5 (death). Response assessment employs standardized criteria to categorize outcomes. The Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 is widely used for radiological evaluation, defining complete response as the disappearance of all s and partial response as at least a 30% decrease in the sum of diameters from baseline. In , pathological response is graded using the Miller-Payne system, which ranges from grade 1 (no reduction in tumor cellularity) to grade 5 (complete pathological response with no residual invasive cancer). Pathological complete response (pCR), defined as the absence of residual invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0), serves as a for improved long-term outcomes in neoadjuvant settings. Assessments occur at baseline, mid-treatment (e.g., after two cycles of ), and immediately before to track progress. For gastrointestinal cancers like , with biopsies is utilized during monitoring to evaluate mucosal response and confirm clinical complete response. Adaptive strategies allow regimen modifications based on interim evaluations; for instance, poor responders may switch from to targeted therapies to improve outcomes. In , risk-adaptive neoadjuvant approaches, as per AUA/ASCO/ASTRO/SUO guidelines, tailor therapy based on patient eligibility and response, potentially escalating or altering treatment for those with inadequate early response. Advanced tools enhance precision in response detection. Positron emission tomography-computed tomography (PET-CT) assesses metabolic changes, with reduced fluorodeoxyglucose uptake indicating favorable response. Liquid biopsies detecting (ctDNA) provide non-invasive monitoring, predicting pCR with high accuracy when combined with in .

Benefits and

Tumor Response and Surgical Outcomes

Neoadjuvant therapy often induces significant tumor responses, measured primarily by pathological complete response (pCR), which indicates no residual invasive cancer in the breast or lymph nodes following treatment. In , neoadjuvant achieves pCR rates ranging from 10% to 40% overall, with higher rates observed in triple-negative (up to 31%) and HER2-positive subtypes (up to 44%). In rectal cancer, neoadjuvant chemoradiotherapy yields complete response rates of 15% to 25%, facilitating tumor downstaging and improved local control. These responses translate to enhanced surgical outcomes by increasing resectability and achieving clearer margins. For , neoadjuvant chemoradiotherapy significantly boosts R0 resection rates (complete resection with negative margins) compared to chemotherapy alone, with meta-analyses reporting odds ratios favoring improved complete resection. In rectal cancer, the approach enables organ preservation, such as sphincter-saving procedures, in approximately 50% to 70% of cases versus lower rates without neoadjuvant treatment, reducing the need for permanent colostomies. Downstaging is a key mechanism, with T-stage reduction occurring in 40% to 60% of responsive cases across various cancers, allowing safer surgical intervention. In , neoadjuvant therapy converts 20% to 30% of borderline resectable tumors to resectable status, with resection rates reaching up to 63% in borderline cases treated with regimens like . Meta-analyses confirm these benefits, demonstrating a 10% to 20% improvement in overall operability and R0 resection rates with neoadjuvant approaches compared to upfront . Additionally, such therapies are not associated with significantly increased postoperative complications, including similar rates of wound infections and major morbidity, without significantly elevating surgical risks. Achievement of pCR serves as a strong predictor of favorable immediate outcomes, particularly in HER2-positive , where it correlates with enhanced event-free survival ( 0.32). Recent advances as of 2025 include the integration of with neoadjuvant , which has shown higher pCR rates, up to 60% in , and improved event-free survival in non-small cell .

Survival and Recurrence Rates

Neoadjuvant therapy has demonstrated comparable overall survival (OS) rates to adjuvant therapy in early breast cancer, with a meta-analysis of over 3,000 patients from ten randomized trials showing no significant difference in 10-year OS (69.6% for neoadjuvant versus 70.2% for adjuvant) or breast cancer mortality. However, achievement of pathologic complete response (pCR) following neoadjuvant chemotherapy serves as a strong prognostic indicator, associated with improved OS; for instance, in triple-negative breast cancer, pCR correlates with a hazard ratio (HR) of 0.24 for death compared to non-pCR cases. In rectal cancer, neoadjuvant chemoradiotherapy significantly reduces local recurrence rates to approximately 5-8%, compared to higher rates without preoperative treatment, contributing to better long-term control. Disease-free survival (DFS) benefits are particularly evident among responders to neoadjuvant therapy, where pCR predicts a 15-20% enhancement in DFS rates; meta-analyses indicate an HR of 0.3-0.5 for recurrence in pCR patients across breast cancer subtypes. By addressing micrometastases early, neoadjuvant approaches alter recurrence patterns, reducing distant metastasis risk; in non-small cell lung cancer (NSCLC), neoadjuvant chemotherapy yields an HR of 0.69 for distant recurrence, corresponding to about a 25-30% relative reduction. Subgroup analyses reveal greater survival advantages in poor-prognosis patients, such as those with node-positive disease in , where neoadjuvant therapy shows trends toward improved OS (e.g., 5-year OS favoring preoperative arm in NSABP B-18 for larger tumors). Meta-analyses from the Early Breast Cancer Trialists' Collaborative Group affirm OS gains from perioperative chemotherapy in high-risk early , with neoadjuvant timing offering equivalent or slightly better outcomes in advanced stages. Despite these benefits, neoadjuvant therapy provides no additional survival advantage in low-risk operable cases, where outcomes mirror those of alone or . In some settings, such as early-stage hormone receptor-positive , OS and DFS remain equivalent to adjuvant approaches without neoadjuvant use. Tumor response, particularly pCR, remains a key predictor of these long-term outcomes.

Risks and Complications

Acute Side Effects

Acute side effects of neoadjuvant therapy encompass a range of short-term toxicities that arise during or shortly after treatment, typically resolving within weeks to months, and are influenced by the modality used—, radiotherapy, or . These effects can impact patient and treatment adherence, with monitoring essential to mitigate risks. In the neoadjuvant setting, where patients are generally fitter at baseline compared to later-stage , the incidence of certain toxicities may be higher due to full-dose regimens administered preoperatively. Chemotherapy-related acute side effects are among the most prevalent. and affect 50-70% of patients, often managed effectively with agents such as antagonists and NK1 inhibitors. , or , occurs in nearly all patients receiving anthracycline- or taxane-based regimens, leading to significant psychological distress but typically reversible post-treatment. Myelosuppression, particularly , develops in 20-30% of cases at grade 3 or higher severity, increasing risk and necessitating supportive interventions. is reported by up to 50% of patients, correlating with treatment cycles and contributing to daily functional impairment. Radiotherapy-associated acute toxicities primarily involve localized reactions in the treatment field. Skin reactions, including and , manifest in up to 95% of patients, graded by intensity and managed with topical emollients or barrier films. , characterized by oral or gastrointestinal , reaches grade 2-3 severity in approximately 30% of cases, leading to pain and nutritional challenges. Diarrhea is particularly common with pelvic , occurring at grade 2 or higher in about 25% of patients, often requiring antidiarrheal medications and dietary modifications. Immunotherapy in the neoadjuvant context introduces immune-related adverse events (irAEs), which stem from dysregulated immune activation. affects 10-20% of patients, presenting as pruritic or maculopapular eruptions responsive to topical corticosteroids. , involving and , occurs in 10-20% at any grade, with higher-grade cases potentially requiring systemic . , manifesting as or , is seen in around 10-15%, monitored through endocrine function tests. Unlike traditional chemoradiotherapy toxicities, irAEs can emerge rapidly and affect distant organs. Management strategies emphasize supportive care to maintain treatment continuity. Dose reductions or delays are employed for myelosuppression, with colony-stimulating factors (G-CSF) used prophylactically in high-risk cases to prevent neutropenia-related complications. For radiotherapy-induced effects, protective and oral rinses alleviate symptoms, while irAEs often resolve with corticosteroids, though severe cases may interrupt therapy. Overall, 10-20% of patients discontinue neoadjuvant treatment due to acute toxicities, with adverse events graded using the Common Terminology Criteria for Adverse Events (CTCAE) to guide interventions and ensure .

Long-Term Consequences

Neoadjuvant radiotherapy can lead to chronic in irradiated tissues, particularly in pelvic malignancies such as rectal cancer, where bowel strictures occur in approximately 5-12% of cases long-term. This arises from progressive scarring and vascular damage, potentially causing intestinal obstruction or requiring surgical intervention years after treatment. Additionally, elevates the risk of secondary malignancies, with an estimated 1-2% incidence at 10 years post-therapy in rectal cancer patients, primarily involving , colon, or rectal sites due to field overlap. Pelvic radiotherapy also poses a substantial risk of , especially in premenopausal women or younger men, through ovarian or testicular damage that often results in permanent sterility. Chemotherapy regimens in neoadjuvant settings contribute to long-term , notably with like , where cumulative doses exceeding 300 mg/m² increase the risk of to around 5% over time, driven by cumulative myocardial . Taxane-based agents, such as , induce persistent in 10-20% of patients, manifesting as chronic sensory deficits that impair daily function and quality of life for years post-treatment. Neoadjuvant immunotherapy, often combined with other modalities, can trigger chronic immune-related adverse events (irAEs), including endocrinopathies like in about 10% of cases, requiring lifelong hormone replacement due to autoimmune . Rarer chronic irAEs encompass autoimmune diseases such as or , affecting a smaller subset but necessitating indefinite monitoring. Interactions between neoadjuvant therapy and heighten certain risks; for instance, in rectal cancer, intervals shorter than 4-5 weeks post-radiotherapy correlate with increased anastomotic leak rates, up to 2-3 times higher, due to impaired tissue healing. Modern techniques mitigate these consequences: intensity-modulated (IMRT) reduces and secondary risks by sparing surrounding tissues, lowering long-term by 20-30% compared to conventional methods. Long-term follow-up protocols, as outlined by organizations like the , recommend serial imaging, cardiac evaluations, and endocrine assessments every 6-12 months for at least 5-10 years to detect and manage these effects early.

Comparison to Other Treatment Approaches

Versus Adjuvant Therapy

Neoadjuvant therapy involves the administration of systemic treatments, such as or targeted agents, prior to primary surgical intervention, allowing it to target the intact and potential micrometastases early in the disease course. In contrast, is delivered postoperatively to address any residual microscopic disease after the bulk of the tumor has been surgically removed, though it may be delayed due to postoperative recovery periods that can extend several weeks. Meta-analyses of randomized trials in have demonstrated equivalent overall outcomes between neoadjuvant and adjuvant approaches, with no significant differences in 5-year rates (hazard ratio approximately 1.00). Similar findings hold for rectal cancer, where systematic reviews of total neoadjuvant therapy versus followed by adjuvant show similar overall but improved disease-free , though neoadjuvant therapy excels in tumor downstaging to facilitate sphincter-preserving . Key advantages of neoadjuvant therapy include its role as an sensitivity test, enabling clinicians to assess tumor response directly and tailor subsequent adjuvant regimens if residual disease persists after . It also promotes higher treatment completion rates compared to due to avoidance of postoperative complications and recovery delays. However, neoadjuvant therapy carries risks such as tumor progression in approximately 4-5% of cases, which may necessitate early surgical intervention and delay planned treatment. Additionally, it can lead to overtreatment in non-responders, exposing patients to without benefiting the . Neoadjuvant therapy is particularly preferred for inoperable or large tumors (e.g., stage II-III or locally advanced rectal cancer) to improve resectability and enable less invasive , while is favored for low-risk cases post-resection where downstaging is unnecessary.

Versus Primary or Definitive Therapy

Primary therapy, also known as definitive or upfront treatment, typically involves direct surgical resection or radiation without preceding systemic therapy and is most suitable for early-stage, operable cancers where the tumor is localized and amenable to complete removal. This approach minimizes treatment delays and is preferred for conditions like stage I breast cancer or T1N0 esophageal cancer, where the risk of micrometastatic disease or incomplete resection is low. In contrast, neoadjuvant therapy is indicated when upfront primary treatment alone carries a substantial risk of incomplete resection or early recurrence, such as in locally advanced disease. For instance, in stage III , neoadjuvant is standard to downstage tumors that may be inoperable or fixed to surrounding structures, enabling breast-conserving in cases where would otherwise be required, unlike stage I disease where primary suffices. Similarly, for T2-T4a esophageal cancers, neoadjuvant chemoradiation is recommended over primary esophagectomy to address nodal involvement and improve resectability, as upfront risks higher rates of positive margins in advanced cases. This rationale stems from multidisciplinary assessments prioritizing tumor biology and extent, with neoadjuvant approaches adopted per NCCN guidelines for such scenarios to optimize long-term control. Neoadjuvant therapy introduces a treatment delay of approximately 4-6 months before , yet clinical trials demonstrate no overall detriment when patients respond adequately, with equivalent to primary in preventing distant recurrence. It enhances surgical outcomes by increasing complete (R0) resection rates; for example, in , neoadjuvant chemoradiation achieves R0 rates of 96.6% compared to 91.2% with primary alone. However, the primary risk of neoadjuvant is progression during treatment, occurring in fewer than 5% of cases, which may necessitate switching strategies, whereas primary avoids this but carries a higher initial risk of positive margins requiring subsequent adjuvant intervention. Patient selection between neoadjuvant and primary involves multidisciplinary tumor boards, with neoadjuvant established as the standard for locally advanced cancers per NCCN recommendations to balance resectability, response assessment, and survival benefits.

Current Research and Future Directions

Key Clinical Trials

In , the NSABP B-18 trial, initiated in 1988 and reported in 1998, compared neoadjuvant anthracycline-cyclophosphamide (AC) chemotherapy followed by to followed by adjuvant AC in patients with operable stage I-III disease, demonstrating similar overall survival (OS) rates at 9 years (69% in both arms) but improved rates of breast conservation (67.8% vs. 60.7% in neoadjuvant vs. adjuvant, respectively). The KEYNOTE-522 phase 3 trial, reported in 2019, evaluated neoadjuvant plus chemotherapy versus plus chemotherapy in high-risk early-stage , achieving a pathologic complete response (pCR) rate of 64.8% in the pembrolizumab arm compared to 51.2% in the arm, establishing integration as a standard. For rectal cancer, the PROSPECT trial, a phase 3 study published in 2023, assessed neoadjuvant alone versus chemoradiotherapy in locally advanced disease prior to , showing non-inferior 5-year disease-free survival (DFS) (80.8% vs. 78.6%; [HR] 0.92, 95% CI 0.74-1.14) while reducing toxicity. The RAPIDO trial, reported in 2020, investigated total neoadjuvant therapy (TNT) with short-course radiotherapy followed by compared to standard long-course chemoradiotherapy in high-risk locally advanced rectal cancer, yielding improved 3-year DFS (77.1% vs. 68.7%; HR 0.67, 95% CI 0.52-0.88). In non-small cell lung cancer (NSCLC), the CheckMate 816 phase 3 trial, reported in 2022, examined neoadjuvant nivolumab plus platinum-doublet chemotherapy versus chemotherapy alone in resectable stage IB-IIIA disease, resulting in a event-free (EFS) of 22.0 months versus 10.0 months (HR 0.58, 95% CI 0.42-0.79). For , phase II trials of neoadjuvant in cisplatin-ineligible patients with muscle-invasive disease have shown promising pathologic downstaging rates and feasibility for in this setting, with updates as of 2024. Recent 2025 updates include ASCO presentations on risk-adaptive neoadjuvant chemotherapy in muscle-invasive , demonstrating tailored approaches that preserve bladder function in responders while maintaining efficacy. Additionally, a 2025 Journal of Medicine report on the KEYNOTE-689 trial in head and neck (HNSCC) highlighted neoadjuvant and adjuvant pembrolizumab with standard care improving EFS (HR 0.70, 95% CI 0.58-0.85) over standard care alone in resectable locally advanced disease. A 2018 meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), synthesizing data from 10 randomized trials involving over 3,000 patients with early , confirmed that neoadjuvant yields equivalent long-term survival to (15-year distant recurrence risk 38.2% vs. 38.0%; mortality 34.4% vs. 33.7%) but enhances locoregional control and surgical options, particularly in high-risk subgroups.

Emerging Modalities and Challenges

Recent advancements in neoadjuvant therapy are exploring innovative modalities to enhance treatment efficacy for solid tumors. approaches, including oncolytic viruses engineered to selectively target cancer cells, have shown promise in early-phase trials when combined with standard neoadjuvant regimens, potentially stimulating antitumor immunity prior to surgery. Similarly, chimeric receptor T-cell (CAR-T) therapies are being investigated in phase I/II trials for neoadjuvant use in solid tumors such as and , aiming to improve tumor infiltration and response rates through localized delivery. Combinations of oncolytic viruses with CAR-T cells have demonstrated synergistic effects in preclinical models, enhancing T-cell persistence and tumor , with ongoing trials evaluating this in neoadjuvant settings for cancers. (AI) models are emerging as tools for predicting neoadjuvant response, using radiomic and genomic data to stratify patients and optimize therapy selection, as evidenced by algorithms achieving up to 85% accuracy in forecasting pathological complete response in cohorts. Biomarker-driven strategies are refining neoadjuvant protocols through real-time monitoring and adaptive designs. Liquid biopsies detecting (ctDNA) enable early assessment of treatment response during neoadjuvant therapy, with ctDNA clearance correlating to improved event-free survival in and cancers. In the I-SPY 2 platform, an adaptive trial framework for neoadjuvant , ctDNA kinetics guide regimen adjustments, allowing escalation or de-escalation based on molecular signals to personalize care and accelerate novel agent evaluation. These approaches facilitate biomarker-enriched enrollment, reducing ineffective treatments and enhancing precision in high-risk subtypes. Despite these innovations, significant challenges persist in neoadjuvant therapy implementation. Overtreatment remains a concern for low responders, with 10-20% of patients experiencing disease progression during therapy, leading to unnecessary and delayed . Access disparities exacerbate inequities, particularly in low-resource settings where advanced testing and novel agents are unavailable, limiting global adoption. Determining the optimal duration of neoadjuvant is unresolved, with debates centering on 2 versus 4 cycles; shorter durations may suffice for responders but risk undertreatment, while longer ones increase immune-related adverse events without proportional gains. Future directions emphasize personalization through to tailor neoadjuvant regimens. Genomic profiling is guiding therapy selection, such as identifying patients likely to benefit from intensified neoadjuvant in , where prior failures highlight the need for refinement. Integration of neoadjuvant hormonal agents with targeted therapies is under exploration despite historical setbacks, focusing on pathway inhibitors to downstage tumors. In the 2025 landscape, strategies for good responders are gaining traction, with trials like EORTC GUCG 2238 testing intermittent deprivation to minimize toxicity while maintaining efficacy in . Global trials are expanding to rare cancers, incorporating neoadjuvant platforms to address unmet needs in sarcomas and neuroendocrine tumors through international collaborations.

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