History of neoadjuvant therapy for rectal cancer

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Abstract

Management of rectal cancer has evolved extensively over the last 30 years. Treatment of locally advanced rectal cancer currently incorporates surgery, chemotherapy, and radiation. Radiation was initially utilized as a salvage method as historic surgical practices were associated with high morbidity rates. In present day, multiple studies have demonstrated that the use of radiation as an adjunct to surgery decreases local recurrence rates. The now routine practice of total mesorectal excision during rectal cancer surgery has further improved outcomes. Numerous studies have evaluated the chemotherapeutic regimens as adjuncts to radiation therapy. Currently, fluorouracil-based regimens are commonly incorporated into neoadjuvant therapy for locally advanced rectal cancer, whereas oxaliplatin has not been incorporated due to more recent studies demonstrating increased toxicity and no clear oncologic benefit. Presently, trials are underway that aim to tailor therapies to specific patterns of disease, in hopes of allowing clinicians to selectively omit components of therapy to limit toxicity and morbidity while maintaining or improving oncologic outcomes. Thus, rectal cancer treatment continues to evolve, and decision-making surround treatment remains highly individualized and nuanced.

Introduction

Treatment of rectal cancer has evolved over the last 30 years. The standard of care in the management of locally advanced rectal cancer (LARC), defined as clinical stage II or stage III disease, includes administration of external beam radiation and chemotherapy followed by surgery and consideration of adjuvant chemotherapy. However, the current climate of rectal cancer treatment is nuanced and individualized. Therapy can be associated with morbidity, and treatment regimens have evolved with the aim of decreasing toxicity and improving outcomes. Additionally, the response to neoadjuvant therapy provides important prognostic information and potentially opens doors for alternative treatment strategies including nonoperative management, sphincter preservation, and local excision.

Section snippets

Radiation as a complement to surgical resection

The first introduction to neoadjuvant radiation therapy for rectal cancer was in 1917 by Janeway and Quick.1 They noted that when radon beads were placed directly into rectal cancers, a significant tumor response was achieved. Surgery was considered a salvage procedure during this time period as the technical and anesthetic requirements to perform surgery were prohibitive.2

As modern surgery became safer, multiple trials in the 1980’s began to detail the risks of radiation and explore the

Evaluation of radiation as neoadjuvant therapy

Shortly after the 1990s, a series of trials was published that looked at the use of neoadjuvant short course radiation (SC-RT) in addition to surgery. The Swedish Rectal Cancer Trial (1997) aimed to examine the role of SC-RT on overall survival. The authors randomized 1168 patients with resectable rectal cancer to SC-RT followed by surgery in one week versus surgery alone. By delivering SC-RT of 5 Gy in five fractions, the overall survival was significantly improved from 30% to 38% (p = 0.008),

Role of radiation in the era of total mesorectal excision

While adjunctive therapies were becoming increasingly utilized, surgeons began to realize that the oncologic outcomes for rectal cancer surgery were highly dependent on surgical technique. Heald's initial prospective case series of 116 patients published in 1986 highlighted the concept of total mesorectal excision (TME) during low anterior resection. Emphasis was placed on sharp dissection under direct vision, excision of the entire mesorectal envelope, avoidance of blunt manual extraction, and

Pre- versus post-operative radiation

Once established by multiple studies that surgery in combination with radiation was more effective than surgery alone for the treatment of LARC,18 timing of the radiataion therapy came into question. Postoperative administration of chemoradiation seemed to be poorly tolerated with higher toxicity, presumably due to irradiation of poorly oxygenated tissues as well as radiation of the neorectum, which carries implications on function. As such, neoadjuvant therapy began to gain acceptance due to

Optimal time to surgery following neoadjuvant chemoradiation

Once preoperative CRT was found to be superior to postoperative therapy, the next question to be answered was the optimal time interval between the completion of neoadjuvant CRT to surgery. The Lyon R90-01 (1999) study compared a period of less than two weeks with six to eight weeks and found improved downstaging with the longer interval.23 The GRECCAR6 trial (2016) randomized patients to either a seven or 11 week interval from CRT (45–50 Gy with fluorouracil or capecitabine) to surgery and

Comparison of short course radiation versus long course chemoradiation

Two prospective randomized trials have demonstrated no oncologic differences between neoadjuvant CRT and neoadjuvant SC-RT. The Polish trial (2006) set out to evaluate these two neoadjuvant regimens directly. A total of 312 patients were randomized to either SC-RT and surgery within seven days or CRT (50 Gy in 28 fractions with bolus 5-FU and leucovorin) followed by surgery four to six weeks later. Early radiation toxicity was higher in the CRT group (18.2% versus 3.2%, p < 0.001). However, no

Optimal chemotherapy regimens in the neoadjuvant setting

Following establishment of preoperative treatment as standard therapy, attention then shifted to trying to determine the optimal combination of sensitizing chemotherapy and radiation in order to achieve the best response while limiting toxicity.

FFCD9203 (2006) was a French trial that aimed to assess the role of adding concurrent chemotherapy consisting of 5-FU and leucovorin to 45 Gy of radiation, followed by adjuvant 5-FU and leucovorin in the treatment of locally advanced middle and distal

Saving radiation in the era of TME and staging MRI

While preoperative radiotherapy had been established to reduce the risk of local recurrence and potentially downstage tumors to increase the rate of sphincter preservation, radiation therapy is also associated with significant side effects. Up to 50% of patient report short term toxicity and long term side effects including autonomic nerve injury, bowel and bladder dysfunction.33 As preoperative staging quality improved with the development of high resolution MRI, there has been increasing

Evolving treatment paradigms

It has been noted that delays in initiation of adjuvant chemotherapy is associated with decreased overall and disease free survival.38 Each four week delay in adjuvant systemic treatment has been correlated with a 14% decrease in overall survival.39 As distant metastases represent the greatest cause of mortality for rectal cancer patients, greater emphasis has been placed on incorporating systemic therapy earlier in the treatment course.

A concept currently being explored is the role of using

Summary

Shifts in the rectal cancer treatment paradigm aim to provide a more tailored approach to patient care, and current studies look to refine the various treatment modalities that have been proposed in the past to optimize outcomes of pathologic and clinical complete response while attempting to limit treatment related toxicity and morbidity. The precise combination of radiation regimens, systemic therapy dosing, and surveillance schedules are still in evolution and are areas of active

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