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Radiation Therapy for Locally Advanced Rectal Cancer

May 17, 2023 - read ≈ 23 min

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Authors

Thomas P. Howard

Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA

Harvey J. Mamon

Department of Radiation Oncology, Brigham and Women’s Hospital, Boston, MA, USA

Content

Introduction

Colorectal cancer is the second most common cancer diagnosed in women and the third most common in men, accounting for nearly 900,000 deaths worldwide each year [1]. While overall incidence has declined, likely due to improved access to screening and pre-malignant polypectomy, the incidence of early-onset colorectal cancer (under the age of 50) continues to rise in many areas of the world [2].

Although not completely understood, both trends likely reflect behavioral changes in relation to modifiable risk factors (Table 1). Genetics play an important role in colorectal cancer, with an overall heritability of 12-35% [1].

Table 1: Risk factors associated with colorectal cancer

Modifiable Risk FactorsNon-modifiable Risk Factors
SmokingAge
Alcohol use Genetic syndromes
High processed and/or red meat consumption Positive family history
Low fiber diet Inflammatory bowel disease
Obesity Type 2 diabetes
Low physical activityMale gender
 Ethnicity

A subset of approximately 5-7% of patients present due to a defined hereditary syndrome, such as familial adenomatous polyposis (FAP) due to mutations in the APC gene, or Lynch Syndrome due to mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2).

Rectal cancer refers to a subgroup comprising ~30% of colorectal cancers, with the distinction purely anatomical in definition. While our knowledge of the molecular and cellular biology underpinning rectal cancer may one day differentiate it from colon cancer, the consensus understanding is that both diseases arise from the same simple columnar epithelia of the gastrointestinal tract. The key difference, then, is that the rectum is confined to the pelvis, a small, confined space that it shares with organs crucial for urinary and reproductive function. Thus, surgical resection is considerably more challenging than removal of any other part of the colon, and local recurrences are associated with higher rates of morbidity and mortality.

Despite the distinction being imperative for clinical decision making, the definition of where the rectum begins proximally remains up for debate [3], with key trials taking different approaches (Table 2).

Table 2: Definitions of the rectum in representative clinical trials

Trial (reference)Definition
GITSG 7175 [5]<12 cm from the anal verge
NCCTG [6]<12 cm from the anal verge or inferior edge extends to sacral promontory
NSABP R-02 [7]“The opening of the pelvic peritoneum was necessary to define the distal extent of the lesion”
Swedish Rectal Cancer Trial [8,9]“Situated below the [sacral] promontory, as shown on a lateral projection on barium enema”
Dutch TME Trial [10]<15 cm from the anal verge and below the level of S1-S2
German Rectal Cancer Trial [11,12]<16 cm from the anal verge
Spanish GCR-3 [13,14]<12 cm from the anal verge
RAPIDO [15]<16 cm from the anal verge
CAO/ARO/AIO-12 [16,17]<12 cm from the anal verge

The most recent United States National Comprehensive Cancer Network (NCCN) guidelines define the rectum “as the portion of bowel located below the pelvic inlet (an imaginary line drawn from the sacral promontory to the top of the pubic symphysis) as determined by a dedicated MRI of the pelvis” [4]. Of note, we are unaware of any major trial that utilized this definition.

The role of radiation therapy in the definitive treatment of rectal cancer is typically limited to locally advanced disease. In this setting, locally advanced describes disease with at least one of the following features:

  • T3 (invades through the muscularis propria into the perirectal soft tissue)
  • T4a (invades into the visceral peritoneum)
  • T4b (invades or adherent to adjacent organs/structures), or positive lymph nodes (as defined radiographically).

Symptoms

Rectal cancer most commonly presents with changes in bowel habits, which can include bleeding (hematochezia), pain, change in caliber, urgency, a sensation of incomplete emptying, and/or tissue prolapse. Associated symptoms can also include lower abdominal pain and weight loss. Lastly, it is not uncommon for rectal cancer to present asymptomatically, with diagnosis at routine screening.

Diagnostic Workup

The first step is digital rectal examination (DRE), as many lower rectal tumors can be palpated. All patients should undergo a colonoscopy that visualizes the entire length of the bowel, as simultaneous primary tumors can be present, particularly in patients with genetic predisposition. If the rectal tumor is completely obstructive at diagnosis, alternatives such as computed tomography (CT) colonography can be used, or the patient needs to be planned for a post-treatment colonoscopy as soon as safely feasible.

Pathology should include staining for mismatch repair genes, as deficiency can qualify the patient for immunotherapy as well as identify a need for germline testing for Lynch Syndrome. Serum studies should include carcinoembryonic antigen (CEA), which is within normal limits in a majority of rectal cancers but, when elevated, can be helpful in monitoring treatment response and for recurrence. All patients should undergo imaging that includes CT of the chest, abdomen, and pelvis for regional and distant staging.

When available, pelvic MRI provides improved resolution with regards to tumor and local nodal staging. For those less familiar with interpretation of these images, our radiology colleagues have created a free online resource:

https://rad.bwh.harvard.edu/mri-rectal-cancer-staging

Endoscopic rectal ultrasound (ERUS) is an alternative to pelvic MRI, with a particular value in T staging, but is highly operator-dependent.

Management

Management of locally advanced rectal cancer has become increasingly complex due to the recent completion of several high-quality clinical trials. Patients are most typically treated with combined modality therapy including surgery, radiation, and chemotherapy. When possible, cases should be discussed in a multidisciplinary fashion with specialists from all three fields.

Surgical intervention for locally advanced rectal cancer is a total mesorectal excision (TME), in which the entire mesorectal fascia is removed en bloc along with the involved rectum. The development of this technique, in the early 1980s, led to considerable improvements in local recurrence rates [18].

The technique took another two decades to be widely adopted, but now is the clear standard-of-care surgical procedure. Two approaches to achieve a TME exist, with the decision based on whether there is sufficient distance between the distal edge of the tumor and the anus to allow for sphincter preservation. This acceptable distance can vary from surgeon to surgeon, and can be impacted by neoadjuvant therapy. A low anterior resection (LAR) is an abdominal-only approach that leaves the anus intact, while an abdominoperineal resection (APR) involves complete resection of the anus.

Historical trials from prior to the widespread adoption of TME established the role of adjuvant chemotherapy and radiation therapy for patients with locally advanced rectal cancer. The GITSG 7175 trial (5) randomized 227 patients to four treatment arms:

  1. No adjuvant therapy
  2. Adjuvant chemotherapy with 5-fluorouracil (5FU) and semustine
  3. Adjuvant radiation therapy
  4. Adjuvant chemoradiation therapy with 5FU.

This study established a significant advantage in disease-free survival in patients treated with combined adjuvant chemoradiation therapy after 80 months of follow-up, which led to a significant improvement in overall survival at 94 months [19].

While the dose of radiation used in GITSG 7175 was low by today’s standards (40 – 44 Gy), a successor trial from NCCTG (6) assessed whether higher dose radiation (45 Gy with an involved field boost to 50.4 Gy) could eliminate the need for chemotherapy. After randomizing 204 patients to radiation alone or combined chemoradiation with 5FU and semustine, they found a significant disease-free and overall survival benefit to the addition of chemotherapy. A third trial, NSABP R-02 [7], assessed the opposite question of whether adjuvant radiation provided any value beyond chemotherapy.

With nearly 700 eligible patients, they found a significant benefit to the addition of radiation therapy in preventing local-regional recurrence, but without an impact on global disease-free or overall survival. Taken together, these trials established a standard-of-care of adjuvant combined chemoradiation therapy for locally advanced rectal cancers.

Around the same time as these adjuvant trials, several groups across Europe were assessing the value of neoadjuvant radiation therapy. The Swedish Rectal Cancer Trial [8,9] evaluated over 900 patients randomized to neoadjuvant short course radiation (25 Gy in 5 fractions) or surgery alone, finding a significant benefit to radiation in improving both local control and overall survival.

The Dutch TME trial [10], which was the first trial to standardize TME surgery and prove that it could be applied outside of the most specialized centers, similarly randomized over 1800 patients to neoadjuvant, short-course radiation or surgery alone. They also found a significant benefit in local control from radiation therapy even with TME, although they did not replicate a difference in overall survival.

The above trials demonstrated the efficacy of either adjuvant or neoadjuvant radiation, but it remained unclear how best to sequence radiation and surgery. The German Rectal Cancer Trial [11,12] gave patients all three modalities – long-course chemoradiation therapy (50.4 Gy in 28 fractions with 5FU, with a 540 cGy boost to the tumor bed in the post-operative group), TME, and adjuvant 5FU – in a different order. They randomized over 800 patients to neoadjuvant chemoradiation or upfront TME, and found improved local control, but not overall survival, in the patients randomized to neoadjuvant chemoradiation.

Interestingly, they found that the difference may be attributable to improved compliance: only half of patients assigned to post-operative chemoradiation received the full dose. In addition, twice as many patients who, at initial surgical evaluation, were expected to need an APR and received neoadjuvant therapy were actually able to have their sphincters preserved, suggesting that neoadjuvant chemoradiation allows for improved organ preservation.

The German Rectal Cancer Trial established that combined chemoradiation should be given prior to surgery, but what about the timing of high-dose chemotherapy? It has been hypothesized that moving chemotherapy earlier into the treatment course could eradicate micrometastatic disease leading to an improvement in overall survival. The Spanish GCR-3 Trial [13,14] treated all patients with long-course chemoradiation, TME, and chemotherapy (capecitabine and oxaliplatin [CAPOX]). They randomized 108 eligible patients to either start or end their treatment sequence with chemotherapy.

As in the German trial, they also found a significant improvement in compliance and toxicities when delivering therapy prior to surgery. There were not, however, higher rates of pathologic complete response (pCR) in patients who received all therapy in the neoadjuvant setting. Furthermore, they did not observe any differences in oncologic outcomes (local control or overall survival), although this Phase II study was not powered for that assessment.

The above trials spawned the era in which we now practice: Total Neoadjuvant Therapy (TNT). But questions on exactly how to deliver TNT remained unanswered. Neoadjuvant therapy was initially established with short-course radiation, but the first TNT trials utilized long-course chemoradiation. In addition, should patients start with high-dose chemotherapy, or with a radiation-based treatment? And lastly, which chemotherapies should be a part of TNT?

Two major studies compared short and long-course radiation as part of TNT. The Polish II study [20,21] randomized over 500 patients to short-course radiation (25 Gy in 5 fractions) followed by consolidative high-dose chemotherapy (5FU and oxaliplatin [FOLFOX]) prior to TME or to long-course chemoradiation (50.4 Gy and FOLFOX) followed by TME, with the possibility of adjuvant chemotherapy depending on facility/provider standards. Their primary endpoint of negative margins at resection was not different between the arms, although they noted lower toxicities in the short-course radiation arm. Of note, an overall survival difference in favor of short-course radiation was noted at 3 years [20], leading to an initial change in practice, but this benefit was no longer seen at 8 years [21], with no difference in oncologic outcomes at longer follow-up.

The second study, RAPIDO [15], randomized over 900 patients with high-risk features by MRI to short-course radiation followed by high-dose chemotherapy (CAPOX or FOLFOX) or to long-course chemoradiation therapy prior to TME, with an option for further adjuvant chemotherapy. Patients in the short-course arm had a reduction in the rate of distant metastases (possibly due to the earlier initiation of high-dose chemotherapy) without a significant difference in local control, although there was a non-significant difference favoring long-course chemoradiation.

There was no overall survival difference between the two groups. Taken together, short-course radiation therapy does not appear to be inferior to long-course chemoradiation across all locally advanced patients, and has the added benefits of convenience and a faster initiation of high-dose chemotherapy.

One major study assessed the order of high-dose chemotherapy and long-course chemoradiation therapy. CAO/ARO/AIO-12 [16,17] randomized patients to start with three cycles of FOLFOX or with long-course chemoradiation, followed by the other, prior to TME. Like preceding trials, they found higher rates of compliance and higher rates of pCR when starting with chemoradiation. Presumably, the improvement in pCR is due to a longer period between completing radiation therapy and undergoing surgery. There were no other differences in oncologic outcomes.

Since multiple trials have found compliance to be highest with the initial therapy, would starting with an even more aggressive chemotherapy added to TNT improve outcomes? PRODIGE 23 [22] randomized patients to neoadjuvant chemotherapy escalation with the addition of irinotecan to 5FU and oxaliplatin (FOLFIRINOX) followed by chemoradiation, TME, and adjuvant FOLFOX versus upfront chemoradiation, TME and a longer course of adjuvant FOLFOX.

In both cases, these are not true TNT regimens given that some of the chemotherapy was given post-operatively. With that said, they found that the neoadjuvant FOLFIRINOX regimen improved both disease-free and metastasis-free survival, but not overall survival.

How do we synthesize all these data to make decisions for our patients?

While recognizing that this field is evolving every few months, as of early 2023, we are comfortable offering short-course radiation as part of TNT for most of our patients. For patients with bulky T3/T4 disease or N2 nodal involvement on imaging, we tend to favor long-course chemoradiation; while RAPIDO did include a high proportion of patients with these characteristics, and there was no significant difference observed at 3 years, we would prefer to see longer-term follow-up data before recommending short-course to our most locally advanced patients. We discuss both short- and long-course options with our patients, recognizing that other factors, such as distance to our treatment facility and convenience, play crucial roles in these decisions.

Whether we are treating patients with short- or long-course radiation therapy, we design our treatment plans based on RTOG guidelines [23]. We obtain a CT simulation for all patients, ideally with a full bladder and in the prone position to move small bowel superiorly out of the treatment field. We give oral contrast to define small bowel, and we insert a soft, radio-opaque catheter into the rectum to define the anal canal clearly on our simulation scans.

We contour a Clinical Target Volume (CTV) that includes the entire mesorectum to cover the internal iliac, pre-sacral, and peri-rectal nodes. For the inferior boundary, this CTV extends to at least 2 cm inferior to the distal extent of the tumor, or to the pelvic floor for lower rectal tumors. If possible, for mid and upper rectal tumors, the CTV excludes the anal canal to reduce the risk of long-term sphincter dysfunction. The anterior boundary extends 1 cm into the nearest fixed structure, which is most typically the full bladder, prostate, or vagina.

The lateral and posterior boundaries extend to either the pelvic musculature or bone, whichever is encountered first. The superior boundary is the sacral promontory in most cases, although this can be extended to 2 cm superior to an upper rectal tumor if needed. We recommend utilizing the RTOG contouring atlas [23] and eContour.org (free with an account registration) to visualize these boundaries. We typically add 7 mm in all directions to obtain our Planning Target Volume (PTV).

For short-course radiation, we deliver 25 Gy in 5 fractions to the entire PTV defined above. For long-course radiation, we deliver 45 Gy to the entire PTV, and an additional 5.4 Gy boost to a cone-down PTV, in a total of 28 fractions. For the cone-down, we typically reduce the volume by ~1 cm each inferiorly and superiorly, if this continues to provide full coverage of the tumor itself. We also reduce the volume by ~1 cm each on both lateral boundaries, with the goal of including the mesorectum and presacral lymph nodes, but not the internal iliac nodes. We do not alter the anterior or posterior boundaries.

Our key organ-at-risk (OAR) safety metric is no more than 5 cc of small bowel receiving 55 Gy for long-course or 27.5 Gy for short-course. In short, this manifests as ensuring no treatment hot spots within small bowel. We also try to limit the volume of small bowel receiving 15 Gy for long-course or 8 Gy for short-course to less than 120 cc whenever possible. Based on these contours and metrics, most of our plans are 3D conformal using four fields, with only a minority needing intensity-modulated radiation therapy (IMRT) to achieve these goals.

The most common side effects that our patients experience are fatigue and diarrhea. Loperamide is effective in most cases, although it is also important to ensure that patients are sufficiently hydrated. With short-course, it is key that patients have follow-up after treatment concludes, as we find that many patients complete all five fractions without any side effects, only to develop moderate-to-severe diarrhea in the week after completing treatment.

Lastly, for patients with near-obstructive tumors at the start of therapy, it is crucial to ensure that they continue to pass stool, as temporary inflammation during treatment can worsen to a true obstruction in some cases, and a small percentage of patients may require a diverting ostomy prior to starting neoadjuvant therapy. Overall, we find that our patients tolerate both regimens well, with a resolution of symptoms in the weeks following treatment.

Controversies/Limitations

While radiation therapy for locally advanced rectal cancer has consistently shown a benefit in reducing local recurrences, no matter the type of surgery or chemotherapy used, it has not as consistently led to a benefit in overall survival across trials. Thus, the value of radiation is debated in the field.

We would argue that the toxicity of a local recurrence in rectal cancer – which often requires a pelvic exenteration with permanent urinary and fecal diversion as well as the removal of the intrapelvic reproductive organs – is more devastating than local recurrence of nearly all other cancers. We discuss these factors openly with our patients to allow them to decide whether they want to undergo radiation therapy.

In addition, there is much nuance in the interpretation of all the trials introduced above. While some endpoints, such as pCR or treatment compliance, are improved with TNT, for example, these markers have not reliably translated into differences in disease-free or overall survival. Furthermore, every trial has different inclusion criteria as well as selection criteria in which patients are considered locally advanced.

We find that certain patients, both in our practice and in interpreting trials, are clearly more or less advanced than others. Although evolving data may one day support short-course for all patients, we still tend to favor more aggressive treatment through long-course chemoradiation for a patient with multiple positive nodes (N2) or nearby organ invasion (T4) clearly visible on CT, as compared to a patient with a small focus of extension through the muscularis propria (T3) only discernable on a high-quality MRI.

Lastly, the next trend in the research and treatment of locally advanced rectal cancer may be whether some patients can avoid surgery entirely. The Organ Preservation in Patients with Rectal Adenocarcinoma (OPRA) trial [24], building on the experience of Dr. Habr-Gama, established a watch-and-wait strategy on the basis of tumor response following TNT, with nearly half of patients avoiding surgical resection at three years.

While encouraging, it is important to note that this trial enrolled a patient population with less advanced disease than other contemporary trials, such as RAPIDO. The successor to OPRA, JANUS, just opened in the United States, primarily to assess whether chemotherapy intensification can improve these results. While we would encourage enrolling appropriate patients on JANUS and eagerly await its results, we do not routinely recommend an organ preservation strategy off trial at the current time.

Summary

Radiation therapy provides an important role in improving local control for patients with locally advanced rectal adenocarcinoma. This field has evolved considerably in just the last few years, leading to numerous ways in which patients can be reasonably treated. We believe that both short-course radiation therapy and long-course chemoradiation therapy have roles in the treatment of selected patients as part of TNT.

References

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