Which Treatment for Which Patient: Rectal Cancer Management After PROSPECT Trial

Determining treatment options for patients with locally advanced rectal cancer after the PROSPECT trial data readout adds an important level to the decision-making process.

Over the past decade, enormous collaborative efforts have completed prospective, randomized, multimodality, locally advanced rectal cancer (LARC) trials with long-term oncologic follow-up.^1-3 Long-term overall survival and disease-free survival across a spectrum of patients with LARC treated with neoadjuvant therapy are promising, and patients have several treatment options available, with increasing emphasis on short- and long-term quality of life (QOL) considerations with preservation of oncologic end points.⁴ The PROSPECT trial results add important data to this end and expand the complexity of the decision-making process.

Clinical Outcomes of the PROSPECT Trial

The phase 2/3 PROSPECT trial (NCT01515787) randomly assigned patients with lower-risk LARC (ie, no clinical/radiographic T4, N2, threatened radial margins [≤ 3 mm], or expectation that an abdominoperineal resection [APR] would be required)to long course chemoradiation, total mesorectal excision (TME), and adjuvant chemotherapy or 6 cycles of preoperative FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) with selective omission of neoadjuvant chemoradiation, TME, and postoperative chemotherapy.³ The results confirmed the noninferiority of the de-escalation experimental approach in which radiation therapy was omitted from the standard trimodality paradigm of LARC treatment. All patients underwent operative resection, however, within the clinical context of avoiding long-term adverse treatment effects secondary to pelvic radiation. Across this large surgical trial, a negative histologic resection margin (R0) rate was achieved in approximately 98% of the per-protocol population. This impressively high R0 rate likely reflects several factors: (1) highly experienced and skilled surgeons, (2) well-selected patients based on rectal MRI (85% utilization reported), and overall, (3) inherently lower-risk rectal cancers.⁵ The notable low local recurrence (LR) rate in the trial (approximately 1%) is concordant with the R0 rate, although it is well recognized that surgical margin status (R0/R1) heavily influences but does not account for all variables responsible for local-regional pelvic recurrence. Along with improvements in surgical technique guided by preoperative MRI, additional tumor-related factors presumably impact LR risk. The excellent local control results reported in PROSPECT treated with neoadjuvant chemotherapy (confirmed > 20% radiographic tumor reduction), TME, and adjuvant chemotherapy for patients with clinically lower-risk LARC is in line with the assertion of Richard J. Heald, MD, decades earlier that a perfect mesorectal excision with sharp dissection preserving the parietal and visceral fascia may be all that is necessary for local control.⁶

For context, population studies analyzing the National Cancer Database have reported an approximate 16% rate of pathologically positive radial margin in patients with clinical stage II or stage III disease managed with neoadjuvant chemoradiation (CRT) followed by low anterior resection.⁵ The R1 resection rate reported in PROSPECT is notably very low (2%), far lower than most reported rectal cancer surgical trials or observational series. This is likely, in part, due to well-selected “lower risk” tumors as well as highly experienced surgeons. Nonetheless, it is also important to recognize that approximately 5% of patients in the experimental arm had disease that was pathologically T4 and/or N2, and 2% of patients in both arms required APR, highlighting the limitations of rectal MRI and clinical staging. These patients with a pathologically higher-risk LARC, although a minority within the trial, may represent missed opportunities, and they otherwise may have benefited from an alternative approach such as total neoadjuvant treatment (TNT).

Investigators in PROSPECT assessed the de-escalation of therapy, pelvic radiation, within the overarching paradigm of LARC treatment for patients with presumed MRI lower-risk rectal cancers. Pelvic radiation results in short- and long-term adverse effects negatively affecting QOL, including sexual, bowel, and bladder dysfunction, which magnifies the surgically induced functional morbidity associated with a low anterior resection with mesorectal excision.³ Additionally, pelvic radiation may result in other long-term adverse effects, including increased secondary malignancies, pelvic insufficiency fractures, and reduced bone marrow reserve. The PROSPECT study results proved that patients with lower-risk LARC can omit radiation safely if sphincter-preserving surgery is feasible after a shared decision-making process without an increase in local disease failure. One of the most feared undertreatment outcomes of withholding pelvic radiotherapy is pelvic disease failure, often unsalvageable and associated with significant morbidity and mortality. PROSPECT data indicate that pelvic radiotherapy for patients with low-risk LARC may be overtreatment for those who are willing to undergo low anterior resection following neoadjuvant chemotherapy; the long-term oncologic follow-up shows no statistical difference in local, distant control or survival at
58 months median follow-up.³

Clinical Relevance of Patient-Reported Outcomes of PROSPECT: Pros and Cons

PROSPECT investigators also evaluated patient-reported outcomes (PROs) as the secondary end point of the study. Notably, PROs at 12 months post resection revealed improved sexual function, fatigue, and less neuropathy when pelvic radiotherapy was omitted, meeting the PROSPECT trial’s prespecified PRO end points.⁷ It is important to recognize that, in the PROSPECT trial, 50% of the tumors in both arms were described as palpable, located at a median of 8 cm from the anal verge. This ranged between 2 cm and 25 cm from the anal verge, indicating some patients underwent an ultralow coloanal anastomosis. Secondly, the definition of the upper/proximal rectum vs the distal colon remains imprecise.⁸ Since the median tumor height was 8 cm from the anal verge, at least half of the patients had an anatomic extraperitoneal (rather than intraperitoneal) LARC, for which oncologic resection necessitates a TME, rather than a partial or tumor-specific mesorectal excision, which is reserved for proximal rectal cancers. An oncologic proctectomy with TME and sphincter preservation transects the distal rectum at the tapered aspect of the mesorectum approaching the levator floor, resulting in a low pelvic colorectal or coloanal anastomosis.

Arguably, the most significant influence on bowel, urinary, and sexual function in patients with rectal cancer is associated with the pelvic dissection and height of the pelvic anastomosis from the anal verge, with more significant low anterior resection syndrome in patients requiring a low pelvic anastomosis. Low anterior resection syndrome is associated with impaired QOL due to fecal incontinence, urgency, frequency, and incomplete bowel evacuation. Bowel dysfunction at 14 years follow-up from the Dutch TME trial reported low anterior resection syndrome in 60% of patients, with 25% reporting major low anterior resection syndrome within the upfront TME arm (ie, no pelvic radiation).⁹ Even a higher anterior rectal resection for intraperitoneal (upper/proximal) rectal cancer with a tumor-specific mesorectal excision unequivocally results in bowel dysfunction in a substantial proportion of patients. A prospective trial evaluating postoperative bowel and genitourinary dysfunction following sigmoid colectomy for neoplasia reported a 1-year postoperative low anterior resection syndrome rate of 28%, 13% with major low anterior resection syndrome, along with significant urinary and sexual dysfunction.¹⁰ Bowel dysfunction is a strong driver of QOL for patients with rectal cancer, and even in the absence of pelvic radiation following resection for an upper or midrectal cancer, approximately 80% of patients report bowel habit–related QOL impairment.¹¹

It cannot be ignored that rectal nonoperative management, also called watch and wait (WW), may represent a therapeutic alternative for many patients and is associated with superior functional outcomes when compared with patients undergoing multimodality treatment(s), including radical resection with mesorectal excision.¹² Rectal organ preservation was achieved in approximately 50% of patients treated with TNT in the phase 2 OPRA trial (NCT02008656), emphasizing the need to account for this possibility in trial design along with a shared decision-making process. In the context of WW, PROSPECT investigators reported a 21.9% pathologic complete response (pCR) following 6 cycles of FOLFOX, similar to the 24% control arm receiving long-course CRT, higher than most rates reported in observational and population trials.¹³ A 21.9% pCR rate in the FOLFOX arm is intriguing, generating the question of whether WW may be safe in clinical complete responses to chemotherapy alone, as it has been increasingly practiced following CRT or TNT. Whether induction chemotherapy alone is sufficient to cure or locally control disease in a subgroup of patients with LARC may be further examined in prospective trials.

A significant number of patients with LARC, including those with a presumed lower-risk LARC, may wish to avoid rectal surgery if feasible. Therefore, establishing an individual’s treatment goals, almost universally cure with preservation of QOL, is expected to become even more complex. Although sphincter preservation was successfully achieved in the majority of patients in the PROSPECT trial and radiation was omitted, some degree of low anterior resection syndrome is anticipated among most, if not all, of these patients, along with reduced bowel-related QOL. The shared decision-making process should include clear dialogue regarding the advantages and disadvantages of each treatment and approach, aligning each patient’s expressed understanding and expectations toward the goals of care.

The PROSPECT trial results create a new treatment alternative for patients with clinically lower-risk LARC. Each component of trimodality treatment for LARC carries the risk of short- and longer-term morbidity and mortality; however, proctectomy with TME remains responsible for the majority of significant long-term effects reducing QOL. Currently endorsed TNT strategies supported by long-term survival data require months of treatments and, therefore, likely risks overtreatment for a substantial proportion of patients without a significant measurable improvement in oncologic outcome. In addition, several patients treated with TNT do not achieve organ preservation due to persistent local or regrowth of disease. Therefore, the PROSPECT trial regimen is a relevant treatment option, in particular for younger patients of reproductive age with long life expectancy hoping to preserve sexual function. Given the increasing incidence of young-onset rectal cancer in Western countries, which is expected to increase over the coming decades by more than 100%, the PROSPECT treatment approach may be ideally suited for this patient subgroup.¹⁴

Discussion: Balancing Treatment Decisions— Who Decides?

Determining which treatments patients need and which may be safely deferred or avoided, including the historical cornerstone of rectal cancer management, proctectomy with TME, is less clear despite the many successes over the past decades. The “best” treatment approach for a specific patient remains out of reach since efforts to escalate or de-escalate treatment with the intent to cure and preserve a patient’s QOL are based on a partial understanding of the biologically heterogeneous behavior and sensitivity to the treatments of rectal cancer.¹⁵ The wide spectrum of tumor response to chemotherapy and radiation across similarly staged LARCs is highly variable, from minimal to complete pathologic regression.¹⁶ Currently, no clinically available tool, test, or biomarker reliably predicts rectal cancer pathologic response to chemotherapy or radiation.¹⁷ As a result, over- and undertreatment, or the ability to truly personalize a treatment strategy by applying escalation or de-escalation considerations, relies largely on MRI rectal staging interpretation. Over the decades, rectal protocoled MRI assessing tumor extent and reproducible radiographic characteristics reflecting higher risk tumor biology (eg, extramural vascular invasion, tumor deposits, deep mesorectal penetration T3c/d/T4, threatened mesorectal fascia, extramesorectal lymph nodes) has been accepted as a reliable clinical tool to estimate each individual patient’s relative risk of local and distant treatment failure following multimodal treatment. However, contemporary clinical risk assessment does not fully depict the biologic variability of rectal cancers to precisely escalate or de-escalate a therapeutic approach, thereby delivering a truly personalized approach, which consequently results in significant clinical and treatment uncertainty.

At this time, the question persists: What should the trade-off be? Treatment escalation in an attempt to potentially preserve the rectum (and de-escalate treatment by deferring radical resection) or, conversely, treatment de-escalation by withholding pelvic radiation to reduce long-term toxicities in presumed lower-risk LARC can complicates management decisions. However, the results of high-quality studies have provided options. Different treatment approaches allow clinicians to better align the expectations, wishes, and concerns of patients to execute an informed, shared-decision treatment plan. This discussion can include objective data from randomized LARC trials to best inform patient decision-making. Nonetheless, it is important to recognize that the increasing complexity of treatment options for patients with LARC may subsequently be more prone to confusion or misunderstanding at the patient and even the
clinician levels.

Conclusion

Collectively, the results from the PROSPECT trial support another effective treatment approach for patients withlower-risk LARC. The PROSPECT results are particularly relevant in light of the increasing incidence of early-onset rectal cancer, for which the long-term effects of radiotherapy may negatively impact the QOL for patients with curable disease. With multiple options for sequencing, intensifying, or de-escalating the multimodal treatment paradigm for patients with LARC, clinician and patient discussions weighing relative risks and benefits to best individualize treatments are more complicated, emphasizing the need for high-level multidisciplinary care and explicit clarity when establishing each patient’s goals of care.

Corresponding Author

Ibrahim Halil Sahin, MD

Assistant Professor of Medicine

Division of Hematology/Oncology,

University of Pittsburgh School of Medicine.

5150 Centre Ave

Pittsburgh, PA 15232 USA

Tel: 412-692-4724

Email: sahinih@upmc.edu

Disclosures

IHS received advisory board fees from Seattle Genetics, GSK, and Lumanity. Research grant from Bayer; SF, advisory board GSK. Research funding supports ViewRay and Natera.

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