new research in rectal cancer

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Rectal cancer disappears for every patient in small experimental drug study

Scientists are hailing the results of a small clinical trial as groundbreaking after a single immunotherapy drug caused every participant's rectal cancer — typically treated with chemotherapy, radiation and surgery — to disappear after six months.

Participants all had stage 2 or 3 rectal adenocarcinoma (meaning the cancer had reached the lymph nodes but hadn't metastasized) with a specific mutation that's particularly sensitive to immunotherapy. They received the monoclonal antibody dostarlimab intravenously every three weeks for six months, a total of nine cycles.

The rectal cancer tumors vanished for all 14 patients who completed treatment — a full clinical remission. The findings were published in the New England Journal of Medicine by researchers at New York City’s Memorial Sloan Kettering Cancer Center (MSK) .

Despite the tiny sample size, the results are promising.

“That’s 100% of patients. We never, ever say that about cancer treatments,” NBC News medical contributor Dr. Natalie Azar said on TODAY Wednesday, calling the findings "unprecedented."

The standard of care for this kind of cancer is usually chemotherapy, radiation and surgery. “As you can imagine, (these) leave people with significant disability, and only about 25% of those folks will have a clinical remission,” Azar said. 

For comparison, researchers found the most common side effects of dostarlimab were rash, itching, fatigue and nausea. “It doesn’t sound fun, but certainly manageable and not life-threatening," Azar said.

Dostarlimab, made by GlaxoSmithKline and also known by its brand name Jemperli, was first approved by the FDA in April 2021 to treat endometrial cancer in adults.

How does immunotherapy for cancer work? 

Immunotherapy works differently from traditional cancer treatments.

“It’s basically harnessing the power of your own immune system to kill cancer cells,” Azar said, unlike chemotherapy, which kills cancer cells but also "a lot of good things." Dostarlimab is a type of drug called a checkpoint inhibitor , which has been used to treat cancer in the past.

However, this trial was the first time researchers were studying the use of dostarlimab alone to treat this subset of rectal cancer patients. “Not all immunotherapy is this dramatically successful,” Azar stressed.

MSK researchers are calling this new approach “immunoablative” therapy, which means immunotherapy is replacing the surgery, chemotherapy and radiation that would otherwise be used to remove cancer.

In theory, any type of cancer that has the same mutation as the MSK patients, also known as mismatch repair-deficient (MMRd) cancer, would be "amenable" to this type of immunotherapy, Azar said. Unfortunately, only 5 to 10% of people with rectal cancer have the mutation targeted by dostarlimab, she added.

Researchers are also studying the drug in early-stage pancreatic cancer, one of the most deadly types of cancer. Other types of cancer that have this mutation include gastrointestinal, breast, prostate, bladder and thyroid .

Azar noted that the drug needs to be studied in more diverse patient populations in settings outside major cities. But the findings are still a reminder of how life-changing clinical trials can be for individual patients and their families.

If you or a loved one has been diagnosed with cancer, she recommended asking your doctor if you have a type of cancer that could benefit from immunotherapy clinical trial.

"Ask those question. Don't wait," Azar said.

Caroline Kee is a health reporter at TODAY based in New York City.

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Innovative treatments for rectal cancer

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By DeeDee Stiepan

Mayo Clinic has been taking care of patients with  rectal cancer  for more than 100 years, dating back to the Mayo brothers. Even at that time, doctors were innovative with their approach to the care of patients with rectal cancer. That continues today as Mayo Clinic offers the latest in minimally invasive surgery.

Eric Dozois, M.D. , a Mayo Clinic colon and rectal surgeon, explains some of the  surgical treatment  options being offered.

Watch: Dr. Eric Dozois discusses innovative treatments for rectal cancer.

Latest minimally invasive techniques

"We're using laparoscopic and robotic platforms to offer patients surgery that is the most up to date in terms of minimally invasive techniques," says Dr. Dozois.

These techniques ensure the least amount of trauma to the patient, while still achieving the goals of surgery which is to remove the cancer.

"What we've shown in our research is that these minimally invasive approaches have decreased complications from surgery. It shortens the length of stay and even reduces the cost of care," says Dr. Dozois.

A multidisciplinary approach

Mayo Clinic Comprehensive Cancer Center 's approach to rectal cancer care is multidisciplinary.

"Every single patient that we take care of with rectal cancer is discussed by a group of physicians and surgeons — medical oncologists, radiation oncologists and colorectal surgeons — because the care of these patients may involve each of those different treatment modalities," says Dr. Dozois.

The care teams can offer individualized care to meet the needs of each patient.

"That's really enhanced the care of patients with rectal cancer, because everybody brings their individual expertise to the discussion. We're all there together. And we can have a good conversation and really tailor what's best for the patient on all those different aspects," he says.

Putting the needs of the patient first

When patients come in for rectal cancer treatment, Dr. Dozois says one of the main concerns patients have is ending up with a  colostomy  bag on the outside of their abdomen.

"Fortunately, we've been able to really develop strategies and approaches through radiation therapy and medical therapy as well as surgery to not only improve their survival, but also to avoid having to have this colostomy bag on the outside," says Dr. Dozois.

He says listening to a patient's concerns and understanding a patient's perspective is an important part of cancer treatment.

"We have a lot of treatment that we can offer. But there are side effects of treatment, there are complications. And so it's really important to have a shared decision-making approach with the patient when it comes to the care of their cancer," says Dr. Dozois.

Learn more about rectal cancer and find a rectal cancer clinical trial at Mayo Clinic.

Join the Colorectal Cancer Support Group on Mayo Clinic Connect.

Also, read this article: " Answers to 4 questions about colorectal cancer treatment and survivorship ."

A version of this article was originally published on the Mayo Clinic News Network .

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New Frontiers in Management of Early and Advanced Rectal Cancer

Simple summary.

Rectal cancer has the capacity to present in a variety of forms. Depending on subtle differences in the characteristics of the tumor, it is possible for the treatment protocol to vary drastically. There are many tools available to optimize patients’ outcomes when treating rectal cancer of these various stages. Advances in early-stage, local presentation of rectal cancer focus on minimally invasive endoluminal surgery. Lesions completely responding to neoadjuvant chemoradiation non-operative surveillance have been explored. For rectal cancers patients with problematic pelvic anatomy, new platforms for resection, such as transanal total mesorectal excision and robotic total mesorectal excision, have been introduced. Late solid organ and peritoneal metastasis, originally thought to be a terminal disease, have undergone recent advances in hepatic and pulmonary metastasectomy, cytoreductive surgery, and intraperitoneal chemotherapy. Understanding these various therapeutic interventions will pave the way for improved patient outcomes.

It is important to understand advances in treatment options for rectal cancer. We attempt to highlight advances in rectal cancer treatment in the form of a systematic review. Early-stage rectal cancer focuses on minimally invasive endoluminal surgery, with importance placed on patient selection as the driving factor for improved outcomes. To achieve a complete pathologic response, various neoadjuvant chemoradiation regimens have been employed. Short-course radiation therapy, total neoadjuvant chemotherapy, and others provide unique advantages with select patient populations best suited for each. With a clinical complete response, a “watch and wait” non-operative surveillance has been introduced with preliminary equivalency to radical resection. Various modalities for total mesorectal excision, such as robotic or transanal, have advantages and can be utilized in select patient populations. Tumors demonstrating solid organ or peritoneal spread, traditionally defined as unresectable lesions conveying a terminal diagnosis, have recently undergone advances in hepatic and pulmonary metastasectomy. Hepatic and pulmonary metastasectomy has demonstrated clear advantages in 5-year survival over standard chemotherapy. With the peritoneal spread of colorectal cancer, HIPEC with cytoreductive therapy has emerged as the preferred treatment. Understanding the various therapeutic interventions will pave the way for improved patient outcomes.

Rectal cancer (cancer within 15 cm from the anal verge) affects approximately 737,000 new patients per year worldwide [ 1 ]. With its wide range and early age of presentation, it is important to understand the alterations in treatment with each stage of presentation. Tumor stage and location drive the management principles of rectal cancer. With surrounding peri-rectal structures vital to the gastrointestinal and genitourinary systems, minor local invasion can have devastating effects on normal physiologic function. Important advances in understanding tumor biology and effective chemotherapy and radiation therapy have led to critical improvements in organ and sphincter preservation rates. Improvements in these therapies have even led to protocols for the avoidance of surgery altogether. It is the purpose of this review article to present a clear and concise discussion on the different treatment options for rectal cancer of various stages and locations.

1. Early Rectal Cancer (Pre-Malignant Polyps, Carcinoma In-Situ, and T1 Carcinoma)

Early-stage rectal cancer includes a variety of malignant and pre-malignant lesions, but what is critical to understand is that the disease process has spread no farther than the muscularis propria. Because of the need for preoperative staging of rectal cancer to guide therapy, stage 1 disease, by definition, possesses no evidence of extraluminal spread on radiologic evaluation. Different modalities are utilized for the assessment of the depth of tumor invasion, but with findings of shallow depth of invasion and no clinically apparent lymphatic spread, the treatment of early-stage rectal cancer can be directed towards endoluminal curative resection. The location of the lesion in relation to the sigmoid takeoff and the valves of Houston can pose difficulties with obtaining the visualization and angulation needed for the surgical resection of the polyp, carcinoma in situ, or cancerous lesion. What is crucial when considering which technique to employ is the consideration of what technique will remove the cancerous lesion in its entirety.

1.1. Transanal Endoscopic Microsurgery (TEM) and Transanal Minimally Invasive Surgery (TAMIS)

Low rectal lesions not suspicious for metastatic spread have traditionally been treated with sphincter sparing transanal endoluminal excision. This transanal endoscopic excision first utilized a conventional anal retractor for the visualization of the tumor or suspicious polyp. This minimally invasive endoscopic technique allows for the miniatous of the rectal reservoir and pelvic innervation and can work to avoid symptoms of low anterior resection syndrome, which have been reported to be as high as 25–80%.

This transanal endoscopic excision was limited by the small endoluminal working space and lack of reach of traditional tools. Buess et al., in 1985, first introduced TEM as a way to obtain surgical resection of these high rectal lesions and reported success in lesions as high as 18 cm from the anal verge in his preliminary group of 33 patients [ 2 ]. This was quickly followed by his follow-up experience with 75 patients, which reported the accurate and non-invasive resection of sessile adenomas and early carcinomas up to 25 cm from the anal verge [ 3 ]. As the surgical envelope has been pushed, TEM and TAMIS have become viable options for the treatment of lesions in the upper rectum. Published data on TEM highlight its ability to provide a more complete specimen than traditional transanal excision with improvements in the fragmented specimen (0% vs. 37%), negative resection margins (98% vs. 78%), and lower recurrence rate (8% vs. 24%) [ 4 ]. These findings were similar to TAMIS when compared with traditional transanal excision as well with a 4% fragmentation rate, 6% microscopic margin positivity, and a 2% recurrence rate. While there is a lack of robust randomized control trials for TAMIS- and TEM-facilitated removal of proximal lesions of the upper rectum, TAMIS and TEM’s reach of three times the traditional conventional anal retractor emphasize their role as an important tool in the colorectal surgeon’s armament.

The indication for the utilization of TAMIS and TEM relies on a discussion with a multidisciplinary team along with a detailed discussion with the patient regarding the risks and benefits of offering local excision without lymphadenectomy. Accurate radiologic or endoscopic assessment of the tumor depth and local and distant metastatic spread is vital for making a sound oncological decision. They are most appropriate for the resection of pre-cancerous lesions, carcinoma-in situ, and superficial (SM1) cT1N0 lesions with favorable clinical and histologic features. Lesions most successfully treated by TAMIS include all lesions (<3 cm) that are typically limited to <30% of the bowel wall circumference. While 3 cm is the recommended size criteria for lesions amenable for TAMIS removal, a small case series demonstrating the success of surgical resection >3 cm has been recorded [ 5 , 6 , 7 , 8 , 9 , 10 ]. TEM and TAMIS involve local excision of the tumor with a full-thickness excision containing the mucosa, submucosa, and muscularis propria. Care is taken to stay in the mesorectal envelope and not injure the peritoneum. If injury to the peritoneum is encountered, the peritoneum is repaired in a single layer incision. Over one-centimeter gross margins on the oncologic sample are recommended for resection with a deep margin of two millimeters [ 11 ].

TAMIS, while able to remove lesions through a minimally invasive approach, has the weakness of not adequately staging the mesorectal lymph nodes. Various classification systems have been identified to stratify lesions based on their depth of invasion of the submucosa, such as the Haggitt and Kudo classifications, for malignant pedunculated and sessile polyps. The ability of these classification systems to delineate high-risk polyps (Haggitt stage 3/4 and SM 2/3) from low-risk polyps (Haggitt stage 1/2 and SM 1) can provide estimates of the risk of concurrent lymphatic spread with malignant polyps, thus guiding the appropriate surgical therapy. Risks of lymphatic spread in SM2/3 sessile polyps and Haggitt 3/4 pedunculated polyps range from 5.8% to13.0%, which represents an unacceptable risk in some patients [ 12 ]. TEM and TAMIS have been selectively studied in rectal cancer with a depth of invasion of T2. Lezoche et al., in 2008, compared their local failure rates, rates of distant metastasis, rates of local and distant failure, and survival in patients with T2 rectal cancer treated with either a total mesorectal excision or by TEM. With a median follow-up time of 84 months, all of these parameters of oncologic success were similar between the two groups demonstrating TEM’s early success in eliminating select local disease confined to the rectum [ 13 ]. These findings were later contradicted by a large meta-analysis of a retrospective study on TEM and TAMIS vs. radical resection. Data on recurrence rates were conflicting with 50% (six studies), demonstrating higher local recurrence rates among patients who underwent local excision. Two additional studies showed no increase in local recurrence rates among patients who underwent local excision of T1 lesions but a significantly higher local recurrence rate among those who underwent local excision of T2 lesions. In 7 of 15 studies, long-term survival was reduced compared with that of patients who underwent radical resection. This prompted the recommendation that TAMIS may be indicated for selected patients with T1 lesions [ 14 ]. Important risk factors for metastatic spread are poorly differentiated tumors, tumor budding on tissue biopsy, lymphovascular invasion, and suspicious lymph node morphology on staging MRI or endoscopic ultrasound. The American Society of Colon and Rectal Surgeons recommends each case be carefully considered for their candidacy based on their histologic findings [ 15 ]. In the case of suspected cT1 without LN metastases, initial transanal full-thickness excision to assess the depth of invasion is reasonable. Patients who are good candidates for abdominal surgery found to have SM2 or SM3 lesions should undergo resection with LN dissection. Similarly, patients found to have T2 cancers should undergo resection with LN dissection.

1.2. Robotic Transanal Minimally Invasive Surgery

With the rise in surgical technology surrounding the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA, USA) and the increased degrees of freedom of the instruments, various studies have been undertaken to identify these platforms’ feasibility facilitating a more effective repair. All have demonstrated no technical difficulties applying the da Vinci Surgical System to the TAMIS setting, but no randomized clinical trials have directly compared robotic TAMIS to traditional TAMIS with laparoscopic tools [ 16 , 17 ]. Additionally, endoscopic submucosal dissection (ESD), an advanced colonoscopic procedure selectively performed by specialized gastroenterologists and colorectal surgeons, can potentially treat lesions with very superficial submucosal invasion (SM1 < 1000 micrometer invasion) in the middle and upper rectum. The technology behind this is relatively novel when compared to TEM and TAMIS, and its application specific to rectal lesions has no clinical practice recommendations [ 15 , 18 ]. Long-term survival rates after ESD for SM1 colon cancer have been demonstrated to be equivalent to that of the anatomical surgical resection. Similar to TAMIS, success with ESD requires careful patient selection [ 19 , 20 ].

2. Locally Advanced Rectal Cancer (Stage 2–3 Disease)

2.1. adjunctive chemoradiation therapy.

In cases when rectal neoplasm has advanced beyond the mucosa and submucosa into the peri-rectal tissue or the perirectal or pelvic sidewall lymph nodes, transanal endoscopic excision is unable to control the oncologic burden of disease. Because of rectal cancer’s localization to the pelvis, the usage of neoadjuvant chemoradiation has emerged as a powerful tool for disease control. The utilization of a combination chemoradiation therapy in the postoperative setting was first introduced in the GITSG 7175 trial in 1985 and demonstrated significant improvements in 7-year local recurrence vs. surgery without adjunctive therapy, radiotherapy in isolation, and chemotherapy in isolation [ 21 , 22 , 23 ]. When overall survival was compared, treatment with chemoradiation demonstrated improved overall survival over surgery alone. This highlighted the benefit of combination chemoradiation therapy in the adjunctive treatment of rectal cancer. The shift of chemoradiation therapy to preoperative therapy was the next landmark advance in the multimodal treatment of rectal cancer. The German Rectal Trial in 2004 evaluated preoperative chemoradiation therapy vs. postoperative chemoradiation therapy with a follow-up duration of 45 months and found that 5-year local recurrence, acute grade 3 and 4 chemotherapy toxicity, long-term toxicity, and the incidence of sphincter sparing surgery were all improved in the group who received preoperative chemoradiation therapy [ 24 ]. These two trials have contributed to shaping the present-day standard of care for adjunctive therapy in rectal cancers.

2.2. Short- vs. Long-Course Radiation Therapy

One recent advance in the adjunctive therapy for rectal cancer centered around the idea that obtaining an expedient potentially curative resection offers the best oncologic outcome over an extended preoperative course of chemoradiation. This minimalization of preoperative adjunctive therapy is postulated to decrease the wait time to oncologic resection, short- and long-term toxicity from chemoradiation, and chemoradiation compliance, without sacrificing long-term survival, local control, and late morbidity. In addition, short-course radiation was touted to be less expensive and a more convenient medium to get patients to their definitive oncologic operation. The Polish I study in 2006 was the first study to compare conventionally fractionated chemoradiation with delayed surgery with short-course irradiation and early surgery [ 25 ]. The results demonstrated that acute radiation toxicity was higher in the chemoradiation group without observable effects on 4-year survival, disease-free survival, local recurrence, sphincter preservation surgery, and severe-late toxicity between short-course radiation and long-course chemoradiation. There was a noticeable difference in the rates of the pathologic complete response (pCR), with the conventional long-course radiation group having a pCR of 16.1% as opposed to 0.7% in the short-course group. Circumferential radial margin positivity was also higher in the short-course radiation group (12.9% vs. 4.4%).

Mirroring this study, the TROG 01.04 trial evaluated T3 tumors within 12 cm from the anal verge who received short-course radiation or traditional long-course chemoradiation [ 26 ]. Compliance rates were higher in the short-course radiation group than the traditional long-course chemoradiation group, with the long-course chemoradiation group giving rise to more adverse events than its short-course radiation counterpart. These included increases in the rates of radiation dermatitis, proctitis, nausea, fatigue, and grade 3/4 diarrhea in the long-course chemoradiation therapy group. The short-course radiation group had lower rates of permanent stoma and anastomotic breakdowns, while the long-course chemoradiation had higher perineal wound complications. When local recurrence was considered, the rates were similar between the two groups but trended towards lower rates in the long-course chemoradiation group (7.5% vs. 4.4%). This trend was intensified with rectal cancers of the lower rectum, with local recurrence rates for long-course chemoradiation reaching 3% vs. 12% in the short-course radiation group.

The choice to go immediately to surgery after short-course radiation was challenged by the Stockholm III trial with the idea that adverse events could be further minimized by delaying surgery 4–8 weeks after the end of the short-course radiation [ 27 ]. Three groups were compared: short-course radiation with immediate surgery within 1 week, short-course radiation with surgery within 4–8 weeks, and traditional long-course chemoradiation. All three groups demonstrated similar rates of local recurrence after 5.2-years of follow-up. When postoperative complications were considered across the three groups, there was no statistical difference in the three groups. When pooled analysis compared patients with short-course radiation with delayed surgery and those with short-course radiotherapy with immediate surgery, short-course radiotherapy with immediate surgery was a risk factor for the development of postoperative complications. This same pooled analysis demonstrated that with short-course radiotherapy with delayed surgery, there was a statistically significant increase in the rate of pCR on the final pathology when compared to short-course radiotherapy with immediate surgery (11.8% vs. 1.7%). This suggests that the delay in surgery may provide additional time for tumor regression more typically attributable to traditional long-course chemoradiation [ 28 , 29 ].

These three randomized, highly powered trials drive the recommendations when attempting to identify patients best suited for short-course radiation. Utilizing these studies and their inclusion criteria, our institutional guidelines maintain that patients with T3 rectal cancer >5 cm from the anal verge, clear circumferential margins on staging MRI/ERUS, or a symptomatic tumor (bleeding or obstructive symptoms) may benefit from short-course radiation and immediate surgery. Those patients with T4, distal tumors (with possible invasion of surrounding structures) will be unlikely to be downstaged to the same degree as short-term radiation with delay or long-course chemoradiation.

2.3. Total Neoadjuvant Chemotherapy

During the past decade, the mortality of rectal cancer could be attributed to its high rate of distant metastasis. Despite the initiation of adjuvant chemotherapy in the postoperative setting, patients continue to be more than twice as likely to present with distant recurrence of the disease than local recurrence [ 30 ]. While long-course chemoradiation has demonstrated the ability to improve local disease recurrence, there exists a paucity of treatment strategies aimed at controlling obscure micrometastases outside the resection margin. With the idea that persistence of treatment with a longer therapy course could lead to more efficacious tumor regression, total neoadjuvant therapy (TNT) was created for the purpose of promoting the elimination of these deadly local and distant micrometastases. Its advantages include enhanced compliance with planned adjunctive therapy, reduction in tumor stage, and targeting of occult micrometastases with exposure to longer courses of chemotherapy preoperatively.

TNT has been selectively researched and studied until 2018, where Cercek et al. completed a large retrospective cohort comparison of traditional chemoradiation patients and TNT patients (8 cycles mFOLFOX with 5 cycles CAPOX (capecitabine and oxaliplatin) or FLOX (weekly fluorouracil/leucovorin and biweekly oxaliplatin) prior to chemoradiation and surgery and no adjunctive chemotherapy [ 31 ]. The TNT group demonstrated a higher rate of minimally invasive surgery (72% vs. 47%) and higher compliance with their chemotherapy regimen (higher average dosages of chemotherapy received, fewer dose reductions, and greater proportions of patients receiving >75% and >90% of their prescribed chemotherapy). TNT patients had higher rates of combined clinical and pathologic complete response (35.7% vs. 21.3%), and the patients managed non-operatively with cCR had no evidence of local tumor regrowth or distance recurrence for at least 12 months. Overall survival and disease-free survival were unable to be assessed by this retrospective study.

The PRODIGE-23 trial was the first large scale trial to prospectively compare traditional long-course chemoradiation with postoperative adjunctive chemotherapy (6 months postoperative modified FOLFOX6 or capecitabine) to TNT (6 cycles neoadjuvant FOLFIRINOX prior to preoperative chemoradiation, followed by surgery and 3 months of adjuvant modified FOLFOX6 or capecitabine) [ 32 ]. With the primary outcome of 3-year disease-free survival and secondary outcomes of pCR, overall survival, and 3-year metastasis-free survival, patients were evaluated with 46.5 months follow-up. The TNT group had higher rates of pCR (27.5% vs. 11.7%), higher 3-year disease-free survival (75.7% vs. 68.5%), and 3-year metastasis-free survival (78.8% vs. 71.7%). Overall survival trended towards a significant change (87.7 vs. 90.8%, p = 0.077) in the TNT group. This demonstrated TNT’s ability to downstage tumors of the rectum and increase disease-free and metastasis-free survival, supporting the theory that TNT was capable of targeting occult micrometastasis responsible for disease progression after surgery.

With the new advances in short-course radiation therapy and the realization that patients could tolerate shorter, more intense bursts of radiation, TNT incorporating short-course radiation therapy was compared to traditional long-course chemoradiation in 2020 by Hospers et al. and van der Valk et al. [ 33 , 34 ]. In this protocol, patients were randomized to either short-course radiation (5 × 5 Gy over a maximum of 8 days), followed by six cycles of CAPOX of FOLOFX4 consolidative chemotherapy, followed by TME or traditional long-course radiation (28 daily fractions of 1.8 Gy up to 50.4 Gy or 25 fractions of 2.0 Gy up to 50.0 Gy) with concurrent capecitabine followed by TME and adjuvant chemotherapy if required (eight cycles of CAPOX or 12 cycles of FOLFOX4).

Compliance with radiation in the short-course radiation TNT group trended higher than in the traditional chemoradiation group (100% vs. 98%), while compliance with chemotherapy demonstrated the same trend with at least 75% of the protocoled chemotherapy being administered in 84% of the short-course radiation TNT and 58% of the traditional chemoradiation group. Rates of grade 3 toxicity in the preoperative setting were higher in the short-course radiation TNT group (48% vs. 25%) but equalized when postoperative grade 3 toxicities were considered in combination (48% vs. 35%). The frequency and severity of postoperative surgical complications were similar between the two groups as well. At the time of resection, pCR rates were higher in the short-course radiation TNT than the traditional long-course chemoradiation group (27.7% vs. 13.8%). Disease-related treatment failure (23.7% vs. 30.4%) and rate of development of distance metastases (19.8% vs. 26.6%) were lower in the short-course radiation TNT group, while locoregional failure (short-TNT: 8.7% vs. traditional: 6.0%) was similar between the two groups.

Questions center around the order of administration of chemoradiation and chemotherapy in these TNT protocols. Fokas et al. designed and completed a multicenter, randomized, phase II trial evaluating pCR, toxicity, compliance, and surgical morbidity [ 35 ]. They compared consolidation chemotherapy after chemoradiation against upfront induction chemotherapy before chemoradiation. They found chemoradiation followed by consolidation chemotherapy had improved rates of pCR (25% vs. 17%), along with better compliance with chemoradiation and less grade 3 or 4 toxicity. Conversely, the compliance with induction/consolidation chemotherapy was higher in the induction chemotherapy group. This was the first study evaluating consolidation vs. induction chemotherapy. While there were significant confounding factors inherent to this study [ 36 ], it begins to answer this important question.

Overall, the literature surrounding TNT has built a strong base for use in rectal cancer. With pooled analysis of the existing data demonstrating clear advantages in pCR rates and early disease-free survival with TNT therapy, it represents a promising strategy in locally advanced rectal cancer [ 37 ]. Patients with T3-4 tumors with N+ disease (especially N2) at high risk for micrometastasis outside the surgical resection field are strong candidates for TNT therapy. Additionally, patients with low-performance status with low-lying rectal cancers, when offered TNT, have the potential to be locally downstaged and undergo a sphincter sparing surgery or be treated with non-surgical management (watch and wait protocol).

2.4. Adjuvant Chemotherapy after Neoadjuvant Chemoradiation

The role of adjuvant chemotherapy in advanced rectal cancer after the administration of neoadjuvant chemoradiation is a topic of controversy. With a third of patients with advanced rectal cancer eventually developing distant metastases, adjuvant chemotherapy is employed to control the spread of disease and eliminate micrometastases still present after surgical therapy [ 24 ]. Despite strong recommendations by the National Comprehensive Cancer Network, American Society of Clinical Oncology, European Society of Medical Oncology, and National Institute of Clinical Excellence, the evidence behind and added beneficial effects of postoperative chemotherapy after neoadjuvant therapy and resection is conflicting. Three large, randomized control trials had been completed to address this question. The first two were completed in 2014 by Coinini and the EORTC Radiation Oncology Group. Coinini observed, in a cohort of 634 patients, no difference in five-year overall survival and disease-free survival. In addition, the rates of distant recurrence were similar between the two groups [ 38 ]. Concurrently, the EORTC Radiation Oncology Group examined 505 advanced rectal cancer patients receiving preoperative radiotherapy with or without chemotherapy. Between the cohort receiving adjuvant chemotherapy group and the cohort being surveilled, there were no differences in the 10-year disease-free survival and no differences in the incidence of distant metastasis [ 30 ]. The third study completed by the Dutch Colorectal Cancer Group a year later mimicked these findings [ 39 ], leading to the question “why do we continue to administer adjuvant chemotherapy?”. With adjuvant chemotherapy significantly impacting quality of life [ 40 ] and compliance rates with adjuvant chemotherapy poor [ 41 ], whether or not to administer postoperative chemotherapy should be given significant thought.

2.5. Watch and Wait Protocol

With the advances in neoadjuvant chemotherapy and the high rates of pCR at the time of resection, one question that has been presented in the literature is, do all cases of rectal cancer need oncologic resection? With certain types of chemoradiation-sensitive tumors that show complete clinical response on repeat imaging and endoscopy, is combination chemoradiation therapy adequate to promote lengthy disease-free survival? With postoperative mortality at 6-months ranging from 2% to 8% and as high as 30% in older patients, are we, as surgeons, doing more harm than good with the resection of a disease that has demonstrated a clinical complete response [ 42 ]? With the significant intestinal, urinary, and sexual dysfunction that comes with a total mesorectal excision, can this significant postoperative morbidity be avoided?

Ongoing trials on patients presenting with a clinical complete response have been undertaken in order to identify the effect on overall and disease-free survival than non-operative management conveys. Non-operative management, deemed the “watch and wait” protocol, was first introduced by Dr. Habr-Gama out of the University of São Paulo and evaluated patients presenting with a complete clinical response. These patients were treated with non-operative management and follow-up [ 43 ]. Patients were defined as complete clinical responders if there was no evidence of disease on clinical, radiologic, and endoscopic studies after the completion of neoadjuvant chemoradiation therapy. Intense surveillance without additional administration of chemotherapy was initiated in this patient cohort to evaluate for both local and distant disease recurrence.

When the patients demonstrating a complete clinical response were compared to non-complete responders receiving surgery and adjuvant chemotherapy, there were no differences in the pre-neoadjuvant staging and disease characteristics. These two groups demonstrated no differences in overall recurrence (watch and wait: 7.0% vs. radial resection: 13.6%) and five-year overall and disease-free survival (watch and wait: 100% vs. radial resection: 88%, 92% vs. radial resection 83%, respectively). On later evaluation at 10-years, the overall and disease-free survival was also similar (watch and wait: 100% vs. radical resection: 97%, watch and wait: 86% vs. radical resection 84%). Only 6.4% of complete clinical response patients treated non-operatively developed systemic recurrence not amenable to curative resection on first presentation. These results were paramount in demonstrating that patients with favorable tumor biology and complete clinical response to neoadjuvant chemoradiation could be non-operatively managed with intensive clinical and radiologic follow-up.

Since 2004, various other studies have come out agreeing with Dr. Habr-Gama’s findings. A recent systematic review and meta-analysis evaluating 23 studies with 867 patients concluded in patients with a complete clinical response managed non-operatively, rates of overall survival and local recurrence are similar to radical resection [ 44 ]. While the detentions of complete clinical response and the surveillance protocols differed widely between these studies, the overall clinical benefit of the watch and wait protocol in select patients is strongly apparent. The watch and wait protocol may play an important clinical role in the management of patients with a no residual clinical disease after neoadjuvant chemoradiation. Further clinical questions center around what to do with this clinical complete response. Some studies advocate for the local excision of the primary tumor. To date, no level 1 data exist evaluating whether local excision of the rectal scar in patients with complete clinical response holds clinical benefit over surveillance. Several studies have attempted to evaluate the rates of local recurrence with local excision of stage II and III rectal cancer after TNT. The GRECCAR2 phase 3 trial, which was designed to assess local excision vs. radical resection after good clinical response to neoadjuvant chemotherapy, failed to identify a superiority of local excision over radical resection in terms of side effects and local recurrence but had significant crossover bias in their study design [ 45 ]. Meta-analysis has attempted to compare local excision to watch and wait, but with the limitations of the study design, conclusions are difficult to compare [ 46 ]. This topic will require future prospective randomized control trials studies to evaluate further before definitive recommendations can be made.

3. Surgical Management of Rectal Cancer

Successful oncologic resection in rectal cancer relies on the surgical tenants of wide local excision of the disease to establish clear margin status and resection of adequate lymph nodes for staging [ 47 ]. The introduction of, and adherence to, complete total mesorectal excision, which is the resection of the total mesorectal envelope containing the local lymphatic drainage of the rectum [ 48 ], has contributed a large part to the improved operative outcomes and long-term survival for rectal cancer patients [ 49 , 50 ]. Notably, total mesorectal excision has produced a notable reduction in rectal cancer recurrence by 30 to 40% [ 51 , 52 ]. The completeness of the mesorectum, as well as other pathologic parameters, such as lymph node harvest and margin involvement, are critical for pathologic staging, prognosis, and subsequent therapy of surgical patients [ 53 , 54 ]. Consequentially, surgical techniques that fail to meet these pathologic standards may be considered inferior to conventional techniques.

The degree of surgical resection depends on the location and circumferential spread of the tumor. The three main resection types for tumors within 15 cm of the anal verge are classified as low anterior resection (LAR) and abdominal perennial resection (APR). Low anterior resection is best utilized for tumors of the rectosigmoid region, where partial or total mesorectal excision is required to obtain an adequate gross margin on the surgical specimen. This surgical distal margin is a continued topic of debate and depends on the height of the tumor in the mesorectal fascia along with its relation to the pelvic floor and anal verge. For proximal, upper rectal cancers tumors in the proximal mesorectal fascial envelope, specific mesorectal excision (partial) is required to obtain a 5 cm gross distal margin. For tumors of the mid-mesorectal envelope, the adequate distal gross margin decreases to 2 cm. Tumors of the distal mesorectal envelope post the greatest difficulty in decision making, as the decision to offer patients sphincter preserving therapy becomes a difficult balancing act with the desire to decrease local recurrence rates. In ultralow anterior resections, the ability to obtain even a 1 cm gross margin in conjunction with a total mesorectal excision has been demonstrated to be an acceptable outcome [ 55 , 56 , 57 ]. The inability to obtain even a 1 cm gross margin with a total mesorectal excision necessitates the utilization of an abdominal perennial resection (APR) and end colostomy.

Further complicating the decision of what surgery to offer is the functional outcome that ultralow anterior resections can confer on a patient’s quality of life. Low anterior resection syndrome (LARS) consists of a constellation of findings, including fecal urgency, incontinence, increased frequency, constipation, feelings of incomplete evacuation, and bowel-emptying difficulties. Short-term symptoms (within 6–12 months of surgery) are usually due to temporary neorectal irritability in the postoperative period and can resolve with time, while long-term symptoms of LARS (extending more than 12 months after surgery) are more likely permanent. The prevalence of LARS is high, with approximately 80–90% of individuals reporting varying degrees of symptoms [ 58 ]. The ability to predict the severity of LARS that a patient will incur with a sphincter preserving operation is still a topic of study in the colorectal landscape and the question of what the overall effect on quality of life, preserving altered, pathologic, and life-altering bowel function as compared to a permanent stoma is vitally important [ 59 ].

3.1. Robotic Total Mesorectal Excision

Laparoscopic surgical resection for rectal cancers has become increasingly popular over the conventional open technique due to positive patient factors, such as decreased pain, lower morbidity, and faster recovery [ 60 , 61 ]. Additionally, the technique has been found to be non-inferior to open techniques in multiple randomized controlled trials in terms of recurrence, overall survival, and disease-free survival [ 62 , 63 ]. With the increasing prevalence of robotic surgery in the United States and the demonstrated efficacy of laparoscopic surgery in the completion of total mesorectal excision, studies evaluating robotic surgery’s role in the treatment of rectal cancer must be explored.

Utilization of the da Vinci Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA) for the completion of a robotically assisted total mesorectal excision has valuable advantages over traditional laparoscopic TME. The use of the robot can allow for an immersive 3-dimensional depth of field, utilization of seven degrees of freedom with its articulating instruments, and a stable camera platform. The first study to evaluate the efficacy of the robot in rectal cancer in a randomized clinical trial setting was completed by the ROLARR Randomized Clinical Trial in 2017 [ 64 ]. This was a randomized clinical trial that included 471 patients from 29 different sites across 10 different countries and evaluated all levels of anterior resection (high vs. low) and abdominoperineal resection. These patients were designated to receive robotic-assisted or conventional laparoscopic TME. With the primary outcome of conversion to open total mesorectal excision and secondary outcomes of circumferential resection margin positivity, quality of life, bladder and sexual dysfunction, and oncological outcomes, this study was the first important tool in quantifying the importance of robotic TME. The conversion rate in the robotic cohort was 8.1%, while the conversion rate in the laparoscopic cohort was 12.2%, which demonstrated a distinct trend towards superiority but did not reach statistical significance (adjusted odds ratio = 0.61 [95% CI, 0.31 to 1.21]; p = 0.16). In addition, none of the other eight reported prespecified secondary endpoints demonstrated statistical differences between the two cohorts. From this data, they concluded the observed benefit of robotic-assisted laparoscopic surgery for rectal cancer did not appear to justify the additional expense of the robot.

Rouanet et al., in 2018, building on the non-significant trend of the ROLARR study to have less conversion to open TME, evaluated their single-center experience with robotic and laparoscopic sphincter sparing total mesorectal excision [ 65 ]. Their data suggested that in sphincter sparing TME, the utilization of the robotic platform resulted in mixed results. There were no differences in overall survival, R1/R0 resection rates, TME grading, length of the distal margin, and circumferential radial margin positivity. There was a difference in the open conversion rate, with robotic TME possessing a conversion rate of 2.0% as opposed to 9.5% found in laparoscopic TME. There were also differences in the median hospital length of stay, with robotic TME patients being more likely to be discharged before postoperative day seven (22% vs. 5.5%). Robotic TME was also associated with a lower number of harvested lymph nodes at pathologic evaluation (15 vs. 19 lymph nodes). From their data, Rouanet et al. concluded robotic surgery, when utilized for patients with difficult anatomy (BMI > 30, low coloanal anastomosis, intertuberous distance under 10 cm, and mesorectal fat area <20.7 cm 2 ), contradicted the ROLARR study by demonstrating superior short-term outcomes and overall survival.

Concurrently, in 2018, a smaller randomized control trial out of the National Cancer Center of South Korea highlighted the advantages of robotic TME [ 66 ]. Their patient population consisted of cT1-3NxM0 patients who were stratified into robotic TME or conventional laparoscopic TME. Outcomes included quality of the TME sample obtained, circumferential and distal resection margins, the number of harvested lymph nodes, morbidity, bowel function recovery, and quality of life. Their randomized clinical trial demonstrated similar rates of conversion to open surgery (1.5% vs. 0%), distal resection margins (1.5 vs. 0.7 cm, p = 0.11), circumferential resection margin positivity (6.1% vs. 5.5%), and rates of complete TME (80.3% vs. 78.1%, p = 0.599). Of interest, there were higher harvested lymph nodes (18 vs. 15 lymph nodes, p = 0.04), which contradicted Rouanet et al.’s retrospective review. Operative times in the robotic cohort were, on average, 112 min longer, but when evaluated in patients with a BMI over 25, the statistical significance disappeared, suggesting that the robot may play a greater role in patients with higher BMI. With similar results in the two groups, they concluded that equivalent outcomes were achievable when comparing robotic TME and laparoscopic TME.

While the operative outcomes appear similar between robotic and laparoscopic TME, several studies have attempted to pool data to identify overall trends. In one meta-analysis, seventeen retrospective reviews and three randomized control trials were combined for analysis [ 67 ]. The collective risk of open conversion statistically favored robotic TME in the retrospective cohort (Odds ratio 0.26 [95% CI, 0.17 to 0.38]), while the randomized control trials trended towards favoring robotic as well (Odds ratio 0.63 [95% CI, 0.35 to 1.13]). Operative time was also statistically longer in both the retrospective reviews and the randomized control trials, with mean differences of 50.35 and 54.4 min, respectively. In the retrospective reviews and the randomized control trials, there were no differences in overall survival, 3-year disease-free survival, local recurrence, lymph nodes harvested, distal margin length, positive circumferential radial margins, and length of stay. With the equivalency of outcomes demonstrated across studies, attention must be turned to the cost implications of performing robotic TME. In a recent meta-analysis combining cost data from robotic and laparoscopic TME, six out of seven studies demonstrated a significantly higher total cost with robotic TME. Four out of four studies in the meta-analysis identified higher operative cost with robotic TME, and zero out of five studies demonstrated no hospital cost savings with robotic TME [ 68 ]. Across the board, robotic TME has been associated with increased healthcare expenditure.

With the equivalent outcomes between robotic TME and laparoscopic TME when universally applied to all patients, one must consider the burden to the healthcare system that robotic surgery conveys. Though no significant outcomes have been identified, robotic TME may play a beneficial role in overweight male patients requiring low coloanal anastomosis.

3.2. Transanal Total Mesorectal Excision

Traditional transabdominal approaches have been primarily utilized for the surgical resection of low to mid-rectal tumors. With the heterogeneity of patient pelvic anatomy, several MRI-based scoring systems for surgical resection difficulty have been proposed to identify patients in whom a traditional top-down dissection would be difficult [ 69 , 70 ]. Factors identified as causing increased surgical difficulty with the traditional transabdominal approach include high BMI, coloanal anastomosis, short distance between the lowest points of the ischial tuberosities, and a large cross-sectional area of mesorectal fat. In mid- and low-rectal cancer, the forward tapering of the mesorectum in the pelvis and forward angle of the distal rectum facilitate a more difficult surgical dissection leading to a greater propensity for incomplete mesorectal excision and involved circumferential resection margins.

As a tool for improved visualization with surgical dissection, a combination transanal transabdominal procedure was first described in 1990 [ 71 ]. This transanal transabdominal procedure was later adapted by Lacy in 2010 to incorporate a single port laparoscopic platform to facilitate better visualization during transanal TME (TaTME) ( Figure 1 and Figure 2 ) [ 72 ]. TaTME has grown in popularity for difficult mid- and low-rectal cancers and can be a powerful tool in sphincter sparing rectal cancer excision. Multiple studies have identified the efficacy of transanal surgical dissection with acceptable postoperative complication rates and TME specimen completeness ranging from 84.0% to 97.1%, but these were small case series and had no direct comparison to the traditional transabdominal approach [ 72 , 73 , 74 , 75 , 76 ]. In the only randomized clinical trial comparing TaTME to traditional transabdominal TME, Denost et al., in 2014, randomized 100 patients with low-rectal cancers (<6 cm from the anal verge) to either TaTME or traditional transabdominal TME [ 77 ]. Their primary outcome was a combination of markers for quality oncologic resection (circumferential resection margin, mesorectum grade, and total lymph nodes identified on pathologic evaluation). When compared, the TaTME group and the traditional transabdominal TME group did not differ by any notable descriptive variables. When outcomes were compared, the rate of positive circumferential resection margin decreased significantly when TaTME was employed (4% vs. 18%, p = 0.025), with no difference in TME quality, morbidity, number of lymph nodes located at pathologic evaluation. Denost et al. concluded that the TaTME approach reduced the risk of positive circumferential resection margin, as compared with the conventional abdominal dissection in low-rectal cancer, suggesting that perineal rectal dissection could become the new standard in laparoscopic sphincter-saving resection for low-rectal cancer. Denost’s study did not evaluate long-term survival, disease-free survival, or local recurrence of the TaTME procedure.

Transanal total mesorectal excision (Coronal).

Transanal total mesorectal excision (Saggital).

TaTME is a powerful tool in facilitating increased visualization of the low-rectal dissection of the distal mesorectum that, in cases of unfavorable pelvic anatomy, traditional transabdominal TME cannot provide. To truly identify TaTME as the preferred method for surgical dissection of low-rectal tumors, long-term oncologic outcomes must be compared to traditional transabdominal TME. The COLOR III trial, created by Deijen et al., has been designed to compare local recurrence, disease-free, and overall survival transanal and laparoscopic TME for mid- and low-rectal cancer with the expected end date of May 2025 [ 78 ]. This will provide much-needed evidence for the adoption of TaTME as a standard therapy for low-rectal tumors with unfavorable anatomy.

4. Distant Solid Organ Metastasis and Peritoneal Carcinomatosis in Rectal Cancer (Stage 4 Disease)

Distant solid organ metastasis and peritoneal carcinomatosis are two presentations of late-stage rectal cancer that carry a poor prognosis. With advances in science and understanding of disease progression, new techniques for the potentially curative resection of these clinical conditions are being explored. With intraperitoneal chemotherapy (IPC) and metastasectomy being introduced for localized disease control, the potential for improvements in overall survival and even the potential for curative resection has been improved [ 79 , 80 ].

4.1. Metastasectomy as a Treatment of Isolated Hepatic Solid Organ Metastasis

Despite standardized population screening protocols, approximately 30% of all advanced rectal cancer patients present with distant metastasis and stage four disease [ 81 ]. With 5-year survival rates of around 8%, care must be taken to identify patients where additional adjunctive therapy has the potential to extend survival and enhance quality of life [ 82 ]. While standard therapy is systemic chemotherapy [ 83 ], 20–30% of patients will have potentially resectable lesions at the time of cancer diagnosis. Identifying patients who have the potential to benefit from surgical resection must take into account tumor biology, total oncologic burden, performance status, and other comorbidities. With 5-year survival of metastasectomy for colorectal cancer being ~30% [ 84 , 85 ] vs. untreated potentially resectable liver lesions being <5% [ 82 , 86 ], notable improvements in survival and quality of life can be obtained with surgical resection.

The proper order of surgical resection of these liver metastasis is poorly understood, and the decision is driven by either eliminating all disease or understanding tumor biology and its effect on overall survival. The traditional approach to synchronous rectal cancer liver metastases has been a staged operation where proctectomy is performed followed by hepatectomy. The benefit of this approach is that it allows for the full metastatic load and biological aggressiveness of the tumor to be identified before the morbidity associated with hepatectomy is encountered [ 87 , 88 , 89 , 90 ]. Traditionally thought to avoid the increased morbidity and mortality from the combination of the two major operations, several studies demonstrated no increased morbidity or mortality when proctectomy is combined with partial hepatectomy [ 91 , 92 , 93 ].

The liver-first approach is the next most commonly employed treatment protocol, with its use being most commonly utilized in locally advanced rectal cancer (T3-4Nx disease). In locally advanced rectal cancer, neoadjuvant chemoradiotherapy can potentially take up to 3 months for completion. The localized radiotherapy may allow surgery on the metastatic disease while treatment for the primary lesion is still ongoing. Evidence supporting the liver-first approach is largely based on non-randomized data but remains strongly in support of the viability of the liver-first approach in patients with advanced hepatic metastasis and asymptomatic primary tumors, as the primary determinant of overall survival is the advanced disease burden in the liver [ 47 , 94 , 95 , 96 ].

4.2. Metastasectomy as a Treatment of Isolated Pulmonary Solid Organ Metastasis

With 1–12% of patients with rectal cancer, developing pulmonary metastasis treatment strategies aimed at improving overall survival must be understood and explored [ 47 ]. Since its first utilization by Blalock in 1944, pulmonary resection for colorectal cancer has become a widely accepted treatment for carefully selected patients [ 97 ]. The current understanding of patients in which pulmonary metastasis benefits overall survival, presented by the NCCN, include patients who may undergo complete resection based on the anatomic location and extent of disease with the maintenance of adequate function, patients whose primary tumor has been resected for a cure, patients whose resectable extrapulmonary metastases does not preclude resection, and patients whose resectable synchronous metastases can be resected synchronously or using a staged approach [ 11 ]. This represents a limited number of patients, with <14% of patients with isolated lung metastasis considered candidates for pulmonary resection [ 98 , 99 ].

These guidelines have limitations due to the design of the previous studies they are based on. Only one study to this point has been designed in the randomized control trial setting due to concerns of a widely accepted treatment practice being withheld from an ideal candidate [ 100 ]. This was the PulMiCC trial, and it was ended early due to poor and worsening recruitment. This trial offered contradictory data as survival did not differ between the patients undergoing pulmonary metastasectomy but without full enrollment and powering of the trial, definitive conclusions could not be drawn. The evidence for pulmonary metastasectomy is overwhelmingly supported by other levels of evidence, such as multi-institutional prospective data registries and systematic reviews of non-randomized or non-comparative studies. One registry, the International Registry of Lung Metastases, established in 1991, encompassed a total of 5206 patients who underwent pulmonary metastasectomy. This registry demonstrated a 5-year survival of 36% when pulmonary metastasectomy could achieve complete resection [ 101 ]. Numerous studies have mirrored the survival benefit found after pulmonary metastasectomy, with 5-year survival rates ranging from 16% to 64%, with the majority of studies citing 30–40% [ 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ], while possible, concurrent resection of hepatic and pulmonary metastasis carry a poor prognosis with 5-year cumulative survival of 0% [ 115 ]. This diverges from pulmonary metastasis observed after hepatic metastasectomy with survival mirroring that is commonly observed in hepatic metastasectomy for colon cancer [ 110 , 115 ]. Several articles have sought to identify differences in the prognosis between pulmonary metastasis from colon and rectal cancer [ 116 ]. Cho et al. demonstrated that rectal cancer while showing no difference in overall survival, did have a worse disease-free survival in the rectal cancer group. Importantly, they also demonstrated differences in the recurrence patterns between rectal and colon cancer, with rectal cancer tending to recur in the lungs as opposed to colon cancer’s predilection for the liver.

While widely believed to be of clinical benefit to colorectal cancer patients presenting with surgically amenable lung metastasis, the role of pulmonary metastasectomy continues to evolve. With no completed randomized clinical trials, surgeons must take into account the full body of literature when evaluating each patient’s candidacy for surgery.

4.3. Intraperitoneal Chemotherapy and Cytoreductive Surgery

With peritoneal spread found in 5 to 10% of patients on initial resection and 50% of patients with recurrent disease, treatment strategies aimed at improving the dismal survival of these patients are necessary [ 117 , 118 , 119 ]. Previously considered a diffuse metastatic disease because of its poor prognosis, a paradigm shift occurred when surgeons began to consider the peritoneal spread of colon cancer as a regional disease spread. With this change in philosophy came changes in treatment patterns suggesting that this disease could be locally resected with improvements in morbidity and survival.

With the introduction of cytoreduction and intraperitoneal chemotherapy to treat the peritoneal spread of colon cancer, intraperitoneal chemotherapy and cytoreductive surgery had undergone several vital improvements. In 1995, Dr. Sugarbaker introduced a stepwise approach to cytoreductive surgery capable of application in a variety of pathologies, giving rise to carcinomatosis. His approach recognized that the peritoneum was a poorly vascularized anatomical structure into which systemic chemotherapy had very limited penetration and efficacy. His approach outlined six separate peritonectomy procedures used in conjunction with intraperitoneal chemotherapy for the removal of localized metastatic disease to the peritoneum ( Figure 3 ) [ 120 ].

Heated intraoperative peritoneal chemotherapy administration.

While being utilized for years for the treatment of abdominal malignancies, the first randomized clinical trial for cytoreduction and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of colorectal cancer origin was completed in 2003 [ 121 ]. Verwaal et al. compared patients with peritoneal carcinomatosis from colorectal primary lesion over a 4-year span. These patients were randomized to cytoreduction and hyperthermic intraperitoneal chemotherapy with adjuvant postoperative chemotherapy or systemic chemotherapy alone without surgery. With the primary outcome of survival, the randomized clinical trial demonstrated survival improvements of 170% with the combination of surgical cytoreduction and intraperitoneal chemotherapy. A maximal benefit was observed in patients with localized disease in under five of the seven abdominal cavity compartments defined by Verwaal.

This stood for years as the primary cited evidence behind the treatment of colorectal peritoneal disease with surgical cytoreduction and HIPEC until Quénet et al. attempted to quantify each component of this combination therapy. Between the cytoreductive surgery component and the hyperthermic intraperitoneal chemotherapy component, Quénet et al. designed the multicenter PRODIGE7 trial to establish each individual component’s survival benefit [ 122 ]. Patients with Peritoneal Cancer Index (PCI) scores under 25 were randomized to cytoreductive surgery with or without oxaliplatin-based HIPEC. After a median follow-up of 63.8 months, their study demonstrated no significant survival or relapse-free survival differences between the cytoreductive surgery plus HIPEC group and the cytoreductive surgery group (41.7 vs. 41.2 months and 13.1 vs. 11.1 months). Surgical morbidity was statistically different between groups with a trend toward grade three or worse 30-day major complications in the combination HIPEC and cytoreductive surgery group (42% vs. 32%, p = 0.083). Overall, 30-day major complications were also statistically significant, with the HIPEC and cytoreductive surgery group having a higher rate of complications (26% vs. 15%, p = 0.035). From the totality of their 6-year study, they concluded that the addition of HIPEC to cytoreductive surgery conveyed no overall survival benefit and increased the risk of developing major postoperative late complications.

With non-invasive imaging strategies possessing disappointing detection rates in nodules smaller than 5 mm in diameter [ 123 ], and the high propensity of peritoneal carcinomatosis to derive from previously resected colorectal cancer, trials evaluating the need for “second-look” surgery to identify peritoneal recurrence were completed. As earlier, less invasive disease treated with cytoreductive surgery conveys a far better prognosis [ 124 ]. Goéré D et al. designed a randomized clinical trial attempting to quantify the benefit of early second-look surgery at 6-months after colorectal cancer resection [ 125 ]. He concluded early second-look surgery with high dose HIPEC oxaliplatin conveyed no advantage in disease-free or overall survival when compared to standard imaging surveillance. In addition, the patients who underwent second-look surgery with high dose HIPEC oxaliplatin had a 41% rate of grade 3–4 complications, highlighting that second-look surgery was not a simple risk-free procedure.

Previously thought to be a contraindication to HIPEC and cytoreductive surgery, what to do in the setting of concurrent peritoneal and liver metastasis has become a focus of recent study. Several studies have identified patients treated with HIPEC with cytoreduction and resection of their liver metastasis and compared their survival to their counterparts receiving modern systemic chemotherapy alone. While the chemotherapy regimen of these concurrent liver metastasis and peritoneal carcinomatosis patients differed between studies, the overall survival was demonstrated to be lower when compared to their isolated peritoneal carcinomatosis counterparts. This signified the poor prognostic outcome of this concurrent spread. When concurrent liver metastasis and peritoneal carcinomatosis patients who were treated with HIPEC, cytoreduction, and liver metastasectomy were compared to patients receiving traditional systemic chemotherapy, median overall survival was improved. This highlighted that this aggressive resection protocol may hold some potential benefit with concurrent liver and peritoneal spread [ 126 ]. This evidence, in combination with multiple systematic reviews, suggest that aggressive resection benefits this patient cohort and that liver metastasis should not be a contraindication for curative resection with HIPEC and cytoreduction [ 127 , 128 ]. However, without the presence of a well-designed randomized control trial, definitive recommendations cannot be made, highlighting the many questions left unanswered surrounding HIPEC and cytoreduction and its ripe potential for future study.

5. Conclusions

With the new and emerging treatment protocols for rectal cancer, it is paramount to have a full understanding of the current literature. It is important to understand in what patient population each tool in the colorectal surgeon’s armamentarium is ideally suited for. With this review, we highlighted transanal endoscopic microsurgery, transanal minimally invasive surgery, the “watch and wait” surveillance protocol, total neoadjuvant therapy, short-course radiation therapy, transanal and robotic total mesorectal excision, pulmonary and hepatic metastasectomy, and cytoreductive surgery with intraperitoneal chemotherapy with the hopes of bringing current research in the field to surgeons’ attention. Understanding these various therapeutic interventions will pave the way for improved patient outcomes moving forward and hopefully stimulate future innovation in the field.

Author Contributions

Contributions to the formulation of this manuscript include: Conceptualization, J.R.W. and S.W.L.; Methodology, J.R.W. and S.W.L.; Literature Review, J.R.W. and S.W.L.; Original Draft Preparation, J.R.W. and S.W.L.; Review and Editing, J.R.W. and S.W.L.; Preparation for Submission, J.R.W. and S.W.L. All authors have read and agreed to the published version of the manuscript.

No funding was used in the creation of this manuscript.

Conflicts of Interest

The authors have no financial interest and no conflict of interests to declare in relation to the content of this manuscript.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

What’s New in Research and Treatment for Rectal Cancer?

Key Takeaways:

• Intensive pre-surgery radiation and chemotherapy are becoming a new standard for treatment for advanced rectal cancer.
• Immunotherapy and cell therapies are in early stages of testing, but researchers believe they have promise for rectal cancer treatment.

The rectum is a six-inch-long portion of the large intestine, which is about five feet in length, but it is the starting point of about one-third of the 145,000 cases of colorectal cancer diagnosed in the United States each year. About 5% of people will develop rectal cancer at some point, and about 11% will be under age 50.

What are the symptoms of rectal cancer?

Nearly all rectal cancer develops from polyps, initially benign growths on the rectal wall. They can be detected and removed by a colonoscopy , reducing the risk of getting rectal cancer, which is why doctors emphasize the importance of undergoing screening colonoscopies, usually beginning at age 45.

Aside from scheduled screening with colonoscopies, rectal cancer can be detected if patients consult their doctors about certain suspicious symptoms, like rectal bleeding or changes in bowel habits.

“Your pattern of bowel habits shouldn’t change much over the course of your life,” says Benjamin Schlechter, MD , a physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber Brigham Cancer Center.

How is rectal cancer treated?

There are special considerations in treating rectal cancer, depending in part on exactly where in the rectum the tumor is located and its pathological stage, and the patient’s age and other medical conditions.

Pathologists classify rectal cancer in four stages:

• In stage I, the tumor has grown below the lining and possibly into the rectal wall.
• Stage II tumors have grown into the rectal wall and may extend into tissues around the rectum.
• In stage III, the tumor has invaded the lymph nodes adjacent to the rectum and some tissues outside the rectal wall.
• Stage IV tumors have spread to distant organs such as the liver or the lungs.

The standard of care for locally advanced rectal cancer (usually stages II and III) has traditionally been neoadjuvant  chemoradiation (given before surgery) and surgery to remove part of the rectum and surrounding tissues, followed by adjuvant chemotherapy. This often requires a colostomy.

Recent clinical trial results of regimens for locally advanced rectal cancer that increase the amount of chemotherapy and radiation given before surgery — a strategy known as “total neoadjuvant therapy” — are changing practice.

“Delaying surgery as long as possible is important,” says Schlechter. “Delays should not be indefinite however. If there’s still cancer two months after total neoadjuvant therapy, surgery is the only safe option.”

According to National Comprehensive Cancer Network guidelines, total neoadjuvant therapy is the preferred regimen for all patients with locally advanced rectal cancer. The aim is to preserve rectal structures in as many patients as possible, for example to allow for normal evacuation rather than a colostomy — or even, in some patients, to avoid surgery.

“It turns out that if chemotherapy is given before or after surgery, the chances of cure are similar. But total neoadjuvant therapy makes it more likely you can avoid the colostomy bag,” says Schlechter.

Total neoadjuvant therapy is also aimed at reducing the chances that the cancer will recur elsewhere in the body by targeting micro-metastases sooner. Micro-metastases are small groups of cancer cells shed by the tumor that spread through the blood or lymph nodes and may cause another tumor to develop.

Schlechter adds that trials have demonstrated that radiation given as the first step in total neoadjuvant therapy achieves the best results. According to the results of the phase 3 RAPIDO clinical trial released at the 2020 American Society of Clinical Oncology Annual Meeting neo-adjuvant short-course radiation therapy followed by chemotherapy should be considered part of the standard of care for treating locally advanced rectal cancer. This approach is quicker than conventional chemoradiation, but it is not clear if surgery can be avoided with this treatment type. The recently published OPRA study looked at two different TNT approaches and specifically investigated whether surgery could be avoided in some people.

Patients on this study were treated with either chemoradiation first then chemotherapy, or chemotherapy first followed by chemoradiotherapy. Overall survival was identical between the two groups, but those who were treated with chemoradiotherapy followed by four months of chemotherapy were more likely to have complete resolution of their tumor. Patients who had complete resolution of there tumor were then given the option to avoid surgery. Importantly, many of those who had a complete resolution had no recurrent cancer and avoided surgery entirely.

Research on new therapies is expanding

“Rectal cancer treatment and research remains an exciting area — there has been a lot happening,” says Schlechter.

He comments that in the past decade, doctors who treat rectal cancer have been learning the best ways to give long-approved drugs and radiation to improve outcomes. More recently, he says, “we’re beginning to try giving targeted drugs, immunotherapy and cell therapies.”

For example, overexpression of the HER2 gene has been detected in about 5% of colorectal tumors. Such tumors are resistant to some standard chemotherapy treatments, such as those that inhibit EGFR. But these tumors are also susceptible to targeting with drugs like trastuzumab and tucatinib, and early clinical trials with anti-HER2 targeted therapy, including some rectal cancer patients at Dana-Farber, have shown promise.

Immunotherapy , which has become a highly effective treatment in some advanced cancers, is also being tested in rectal cancer.

In one widely publicized but very small study, treatment with dostarlimab, a drug that blocks the PD-1 immune checkpoint in cancer cells achieved a complete response of locally advanced rectal cancer in 12 patients whose tumors were DNA mismatch-repair deficient, meaning that their DNA lacks the ability to repair certain cell mutations. Although it was a dramatic outcome with single-agent immunotherapy, researchers emphasize that only about 5 to 10% of rectal cancers have this genetic makeup, and the follow-up of the 12 patients in the trial has been relatively short.

Another form of immunotherapy, CAR T cells , in which the patient’s immune cells are modified to be more effective at identifying and killing cancer cells is also in clinical trials for rectal cancer. At this point, says Schlecter, “we will have many trials for cellular therapy, but we have a long way to go” before the role of immunotherapy in rectal cancer is established.

About the Medical Reviewer

Dr. Schlechter is a medical oncologist who specializes in gastrointestinal cancers including colorectal cancer, anal cancer, pancreatic cancer, and neuroendocrine cancers, among others. He is a former intern, resident, chief resident and fellow at Beth Israel Deaconess Medical Center as well as a member of the faculty at Harvard Medical School. In the past he was the Director of Inpatient Hematology and Oncology at Beth Israel Deaconess Medical Center as well as the Assistant Program Director of the Internal Medicine Residency Program. His work at Dana-Farber focuses on providing excellent patient care while trying to advance the treatment of gastrointestinal cancer patients.

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Immunotherapy with two novel drugs shows activity in colorectal cancer

A combination of two next-generation immunotherapy drugs has shown promising clinical activity in treating patients with refractory metastatic colorectal cancer, a disease which has not previously responded well to immunotherapies, according to a Dana-Farber Cancer Institute researcher.

The results of an expanded phase 1 trial of the two drugs, botensilimab and balstilimab, are to be presented at the ASCO Gastrointestinal Cancers Symposium Jan. 19-21 in San Francisco. The study is led by Benjamin L. Schlechter, MD , a senior physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber.

The trial included 70 patients with metastatic colorectal cancer who had been previously treated with several lines of drugs, including immunotherapies. These patients all had tumors termed microsatellite stable, or MSS, meaning that their genes for repairing certain types of DNA damage were intact. MSS colorectal tumors account for the vast majority of colorectal cancers, and the first generation of immunotherapy drugs have had little effect on them. While immunotherapy has succeeded in microsatellite unstable (MSI) colorectal cancers, only about 3-5% advanced colorectal cancers are MSI and there are no approved immunotherapies for the far more common MSS colorectal cancers.

The two-drug combination being tested in the expanded phase 1a/1b trial of patients with metastatic MSS colorectal cancers were novel, next-generation antibodies. Botensilimab is an antibody directed against the T-cell receptor cytotoxic T-lymphocyte-associated antigen 4, or CTLA-4, which is an immune checkpoint that regulates T-cell activation. Balstilimab is a novel monoclonal antibody designed to block PD-1 – another immune checkpoint protein – from interacting with PD-L1 and PD-L2. By inhibiting this interaction, balstilimab is aimed at freeing the immune system to attack cancers.

The patients in the trial were followed for a median of 7 months after receiving the drug combination. During that period, 23% of the patients had a reduction in the size of their tumors, and the median duration of response was not reached. The disease control rate – the percentage of patients with metastatic cancer who had a complete or partial response and stable disease – was 76%. The 12-month overall survival was 63%. The main population of patients who benefited from the combination were those who did not have active metastatic cancer in their liver.

Treatment-related adverse events occurred in 91% of patients, including grade 3 in 40% and grade 4 in 3%. Twelve percent of patients discontinued both drugs because of adverse events.

The researchers concluded that “in patients with heavily pretreated metastatic MSS colorectal cancer, botensilimab plus balstilimab continues to demonstrate promising clinical activity with durable response, and was well tolerated, with no new immune-mediated safety signals.”

“Harnessing the power of immune therapy in refractory colorectal cancer has been a key goal of multiple clinical trials in advanced colorectal cancer, but in MSS colorectal cancer efforts have been universally disappointing,” said Schlechter. “These data are a meaningful and important advance in the care of this very sick population.”

Based on these findings, a randomized phase 2 trial in patients with MSS colorectal cancer is currently enrolling.

Funding for this research comes from Agenus, Inc.

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Rectal cancer: researchers hail ‘breakthrough’ experimental treatment

Every patient treated with immunotherapy drug went into remission, researchers in New York reported

Every patient treated for rectal cancer with an experimental immunotherapy drug went into remission, in findings that researchers have hailed as a breakthrough.

All 14 patients who were given the new drug, dostarlimab, were found after six months to have no trace of cancer. Researchers at Memorial Sloan Kettering cancer center in New York could find no sign of the disease through physical examination, endoscopies, MRIs or other scans.

The researchers described the results, published in the New England Journal of Medicine , as “breakthrough findings” and said they were astonished by the universal success rate. “ I believe this is the first time this has happened in the history of cancer,” Dr Luis Diaz, a leading member of the team, told the New York Times .

For the patients involved – and potentially for other patients with specific types of rectal cancer who come after them – the outcome was dramatic. It allowed them to avoid further surgery, chemotherapy and radiation, proceeding under observation alone.

That could have far-reaching implications, particularly for young adults.

“Surgery and radiation have permanent effects on fertility, sexual health, bowel and bladder function and the implications for quality of life are substantial, especially in those where standard treatment would impact childbearing potential,” another lead researcher, Dr Andrea Cercek, said. “As the incidence of rectal cancer is rising in young adults, this approach can have a major impact.”

Dostarlimab has been developed by the pharmaceutical company GlaxoSmithKline. The drug was given to the patients every three to six months at a cost of $11,000 each dose.

The drug is known as a checkpoint inhibitor. It works by removing the shield that cancer cells put around them that blocks T-cells in the body’s immune system from attacking them.

Without the shield, the cancer cells are exposed to the immune system and vulnerable to being destroyed.

The findings fall within one of the most promising areas of frontier experimental cancer research that combines personalised medicine with immunotherapy. The ambition is to train the immune system to destroy cancer cells by helping it detect specific mutations in the genetic makeup of an individual patient’s own tumour.

The Sloan Kettering researchers designed the clinical trial to apply to a specific sub-group of renal cancer patients. All 14 patients had a rare mutation in their tumour cells known as “mismatch repair deficiency”, meaning that the cells’ DNA repair system is not working.

As a result, the cancer cells produce proteins with higher levels of genetic errors in them which makes them more visible to the body’s immune system once the shield has been removed.

The scientists involved in the dostarlimab trial are at pains not to present the findings as a cure. The patients will be kept under close medical assessment to see how long they remain cancer-free.

But they are optimistic about these first results. Diaz said the new treatment would be “practice-changing” for people with the relevant type of rectal cancer.

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A Cancer Trial’s Unexpected Result: Remission in Every Patient

The study was small, and experts say it needs to be replicated. But for 18 people with rectal cancer, the outcome led to “happy tears.”

By Gina Kolata

It was a small trial, just 18 rectal cancer patients, every one of whom took the same drug.

But the results were astonishing. The cancer vanished in every single patient, undetectable by physical exam, endoscopy, PET scans or M.R.I. scans.

Dr. Luis A. Diaz Jr. of Memorial Sloan Kettering Cancer Center, an author of a paper published Sunday in the New England Journal of Medicine describing the results, which were sponsored by the drug company GlaxoSmithKline, said he knew of no other study in which a treatment completely obliterated a cancer in every patient.

“I believe this is the first time this has happened in the history of cancer,” Dr. Diaz said.

Dr. Alan P. Venook, a colorectal cancer specialist at the University of California, San Francisco, who was not involved with the study, said he also thought this was a first.

A complete remission in every single patient is “unheard-of,” he said.

These rectal cancer patients had faced grueling treatments — chemotherapy, radiation and, most likely, life-altering surgery that could result in bowel, urinary and sexual dysfunction. Some would need colostomy bags.

They entered the study thinking that, when it was over, they would have to undergo those procedures because no one really expected their tumors to disappear.

But they got a surprise: No further treatment was necessary.

“There were a lot of happy tears,” said Dr. Andrea Cercek, an oncologist at Memorial Sloan Kettering Cancer Center and a co-author of the paper, which was presented Sunday at the annual meeting of the American Society of Clinical Oncology.

Another surprise, Dr. Venook added, was that none of the patients had clinically significant complications.

On average, one in five patients have some sort of adverse reaction to drugs like the one the patients took, dostarlimab, known as checkpoint inhibitors. The medication was given every three weeks for six months and cost about $11,000 per dose. It unmasks cancer cells, allowing the immune system to identify and destroy them.

While most adverse reactions are easily managed, as many as 3 percent to 5 percent of patients who take checkpoint inhibitors have more severe complications that, in some cases, result in muscle weakness and difficulty swallowing and chewing.

The absence of significant side effects, Dr. Venook said, means “either they did not treat enough patients or, somehow, these cancers are just plain different.”

In an editorial accompanying the paper, Dr. Hanna K. Sanoff of the University of North Carolina’s Lineberger Comprehensive Cancer Center, who was not involved in the study, called it “small but compelling.” She added, though, that it is not clear if the patients are cured.

“Very little is known about the duration of time needed to find out whether a clinical complete response to dostarlimab equates to cure,” Dr. Sanoff said in the editorial.

Dr. Kimmie Ng, a colorectal cancer expert at Harvard Medical School, said that while the results were “remarkable” and “unprecedented,” they would need to be replicated.

The inspiration for the rectal cancer study came from a clinical trial Dr. Diaz led in 2017 that Merck, the drugmaker, funded. It involved 86 people with metastatic cancer that originated in various parts of their bodies. But the cancers all shared a gene mutation that prevented cells from repairing damage to DNA. These mutations occur in 4 percent of all cancer patients.

Patients in that trial took a Merck checkpoint inhibitor, pembrolizumab, for up to two years. Tumors shrank or stabilized in about one-third to one-half of the patients, and they lived longer. Tumors vanished in 10 percent of the trial’s participants.

That led Dr. Cercek and Dr. Diaz to ask: What would happen if the drug were used much earlier in the course of disease, before the cancer had a chance to spread?

They settled on a study of patients with locally advanced rectal cancer — tumors that had spread in the rectum and sometimes to the lymph nodes but not to other organs. Dr. Cercek had noticed that chemotherapy was not helping a portion of patients who had the same mutations that affected the patients in the 2017 trial. Instead of shrinking during treatment, their rectal tumors grew.

Perhaps, Dr. Cercek and Dr. Diaz reasoned, immunotherapy with a checkpoint inhibitor would allow such patients to avoid chemotherapy, radiation and surgery.

Dr. Diaz began asking companies that made checkpoint inhibitors if they would sponsor a small trial. They turned him down, saying the trial was too risky. He and Dr. Cercek wanted to give the drug to patients who could be cured with standard treatments. What the researchers were proposing might end up allowing the cancers to grow beyond the point where they could be cured.

“It is very hard to alter the standard of care,” Dr. Diaz said. “The whole standard-of-care machinery wants to do the surgery.”

Finally, a small biotechnology firm, Tesaro, agreed to sponsor the study. Tesaro was bought by GlaxoSmithKline, and Dr. Diaz said he had to remind the larger company that they were doing the study — company executives had all but forgotten about the small trial.

Their first patient was Sascha Roth, then 38. She first noticed some rectal bleeding in 2019 but otherwise felt fine — she is a runner and helps manage a family furniture store in Bethesda, Md.

During a sigmoidoscopy, she recalled, her gastroenterologist said, “Oh no. I was not expecting this!”

The next day, the doctor called Ms. Roth. He had had the tumor biopsied. “It’s definitely cancer,” he told her.

“I completely melted down,” she said.

Soon, she was scheduled to start chemotherapy at Georgetown University, but a friend had insisted she first see Dr. Philip Paty at Memorial Sloan Kettering. Dr. Paty told her he was almost certain her cancer included the mutation that made it unlikely to respond well to chemotherapy. It turned out, though, that Ms. Roth was eligible to enter the clinical trial. If she had started chemotherapy, she would not have been.

Not expecting a complete response to dostarlimab, Ms. Roth had planned to move to New York for radiation, chemotherapy and possibly surgery after the trial ended. To preserve her fertility after the expected radiation treatment, she had her ovaries removed and put back under her ribs .

After the trial, Dr. Cercek gave her the news.

“We looked at your scans,” she said. “There is absolutely no cancer.” She did not need any further treatment.

“I told my family,” Ms. Roth said. “They didn’t believe me.”

But two years later, she still does not have a trace of cancer.

Using information provided by a patient, an earlier version of this article misstated which year a participant in a drug trial was diagnosed with rectal cancer. Sascha Roth was diagnosed in 2019, not 2018.

How we handle corrections

Gina Kolata writes about science and medicine. She has twice been a Pulitzer Prize finalist and is the author of six books, including “Mercies in Disguise: A Story of Hope, a Family's Genetic Destiny, and The Science That Saved Them.” More about Gina Kolata

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This experimental drug could change the field of cancer research

Sacha Pfeiffer

Jonaki Mehta

The new treatment is categorized as immunotherapy. skaman306/Getty Images hide caption

The new treatment is categorized as immunotherapy.

A tiny group of people with rectal cancer just experienced something of a scientific miracle: their cancer simply vanished after an experimental treatment.

In a very small trial done by doctors at New York's Memorial Sloan Kettering Cancer Center, patients took a drug called dostarlimab for six months. The trial resulted in every single one of their tumors disappearing. The trial group included just 18 people, and there's still more to be learned about how the treatment worked. But some scientists say these kinds of results have never been seen in the history of cancer research.

Dr. Hanna Sanoff of the University of North Carolina's Lineberger Comprehensive Cancer Center joined NPR's All Things Considered to outline how this drug works and what it could mean for the future of cancer research. Although she was not involved with the study, Dr. Sanoff has written about the results.

This interview has been lightly edited

On her first reaction to the results: I mean, I am incredibly optimistic. Like you said in the introduction, we have never seen anything work in 100 percent of people in cancer medicine.

On how the drug works to treat cancer: This drug is one of a class of drugs called immune checkpoint inhibitors. These are immunotherapy medicines that work not by directly attacking the cancer itself, but actually getting a person's immune system to essentially do the work. These are drugs that have been around in melanoma and other cancers for quite a while, but really have not been part of the routine care of colorectal cancers until fairly recently.

On the kinds of side effects patients experienced: Very, very few in this study - in fact, surprisingly few. Most people had no severe adverse effects at all.

On how this study could be seen as 'practice-changing': Our hope would be that for this subgroup of people - which is only about five percent to 10 percent of people who have rectal cancer - if they can go on and just get six months of immunotherapy and not have any of the rest of this - I don't even know the word to use. Paradigm shift is often used, but this really absolutely is paradigm-shifting.

On why the idea of being able to skip surgery for cancer treatment is so revolutionary: In rectal cancer, this is part of the conversation we have with someone when they're diagnosed. We are very hopeful for being able to cure you, but unfortunately, we know our treatments are going to leave you with consequences that may, in fact, be life-changing. I have had patients who, after their rectal cancer, have barely left the house for years - and in a couple of cases, even decades - because of the consequences of incontinence and the shame that's associated with this.

On next steps for the drug: What I'd really like us to do is get a bigger trial where this drug is used in a much more diverse setting to understand what the real, true response rate is going to be. It's not going to end up being 100 percent. I hope I bite my tongue on that in the future, but I can't imagine it will be 100 percent. And so when we see what the true response rate is, that's when I think we can really do this all the time.

This piece was reported by Sacha Pfeiffer, produced by Jonaki Mehta and edited by Kathryn Fox. It was adapted for the web by Manuela Lopez Restrepo.

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Promising rectal cancer study

UNC Lineberger Comprehensive Cancer Center's Hanna K. Sanoff, MD, MPH, is the author of a viewpoint in the New England Journal of Medicine that provides a perspective on the evolving treatment of rectal cancer. She offers prospects for future treatment of the disease in light of encouraging findings from a study published in the journal that found the immunotherapy drug dostarlimab was especially effective in a phase II clinical trial of a dozen patients with a subtype of rectal cancer.

Approximately 5-10% of rectal cancers are molecularly characterized as being deficient in mismatch repair enzymes (dMMR). These cancers tend to be less responsive to chemotherapy and radiation, which increases the chance that surgical treatment is necessary. Unfortunately, surgery can result in notable health consequences, including nerve damage, infertility, and bowel and sexual dysfunction.

"Over 45,000 people in the United States were diagnosed with rectal cancer last year, and many of those cases were in people under the age of 65. Historical treatment of the disease has included radiation, surgery and chemotherapy, which can be debilitating despite its curative potential, pointing to the need for better and more effective treatments that can prolong longevity while maintaining quality of life," said Sanoff, who is the quality and innovation officer of the North Carolina Cancer Hospital and professor in the UNC School of Medicine Division of Oncology. "These initial findings of the remarkable benefit with the use of dostarlimab are very encouraging but also need to be viewed with caution until the results can be replicated in a larger and more diverse population."

Sanoff also cautioned that little is known about how long the benefit of the drug will last or whether it will be curative in the long-term. Patients in this trial have only been observed for six months to two years so far.

"The responses in these first 12 of a planned-for 30 patients in the trial were remarkable and exceed what we would expect with the standard chemotherapy plus radiation," Sanoff said. "Although quality of life measures have not been reported yet, it's encouraging that some of the most difficult symptoms, such as pain and bleeding, all resolved with the use of dostarlimab."

Sanoff noted there are other immunotherapy drugs that could also be tested against this form of rectal cancer. "As a gastrointestinal medical oncologist, I can think of nothing better for my patients than being able to offer them a drug that is more effective, less toxic and avoids surgery, chemotherapy, and radiation; that day can't come soon enough," she said.

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Advances in Colorectal Cancer Research

Colorectal cells grown into organoids, stem cell-derived human 'mini-organs' that are used to study human development and disease.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat colorectal cancer. They are also looking at what factors influence screening behaviors, how to address disparities, and the rising rates of colorectal cancer in younger people.

This page highlights some of the latest colorectal cancer research, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and findings from recent studies.

Prevention and Early Detection

Screening can prevent colorectal cancer through detection of precancerous growths, or polyps , which can be removed before they become cancerous. It can also allow colorectal cancers to be detected early, before they cause symptoms and when treatment may be more effective.

Colorectal cancer screening tests. These include colonoscopy , sigmoidoscopy , stool-based tests to detect hidden blood ( fecal immunochemical test ing (FIT) or fecal occult blood testing (FOBT)), and virtual colonoscopy . (See Screening Tests to Detect Colorectal Cancer and Polyps for more information.)

Despite the availability of effective colorectal cancer screening tests, some people choose not to get screened. Some reasons may be because of the personal nature of the procedures, a lack of recommendation by their doctor, perceived costs or lack of insurance, or the preparation involved for a colonoscopy.

Can Colorectal Cancer in Younger Adults Be Found Early?

Researchers find four “red flag” signs that may identify colorectal cancer early in younger adults.

Although not currently recommended for screening, there are new techniques under development such as:

• finding technologies that improve the genetic analysis of stool samples, which may reveal the presence of tumor DNA
• looking at changes in the gut microbiome and trying to identify specific bacteria that could potentially help identify patients at risk for colorectal cancer

Repeat screening or follow-up . The guideline for getting a screening colonoscopy is every 10 years. However, people who have noncancerous polyps detected at colonoscopy are generally asked to return for a repeat colonoscopy earlier than that.

NCI’s FORTE Colorectal Cancer Prevention Trial , is now looking at whether some people with one or two small polyps can wait 10 years before returning for another colonoscopy. By comparing two study groups, one with repeat colonoscopy after 5 years, and one with repeat colonoscopy after 10 years, researchers hope to learn whether waiting 10 years is as good at preventing colorectal cancer as follow-up exams after 5 years. 

For colorectal cancer screening to be effective, people need to follow up on abnormal test results. In one study, researchers found that people who had a positive at-home stool test to screen for colorectal cancer, but did not have a follow-up colonoscopy , were twice as likely to die from colorectal cancer as those who did have a follow-up colonoscopy.

NCI is funding research to better understand the many factors that can contribute to why a person may not have a follow-up test and how to increase repeat screening and follow-up colonoscopy after abnormal stool tests. Researchers are also studying how the many levels of the healthcare delivery system affect the decision to get screened.

Treatment for Colorectal Cancer

Surgically removing the cancer is the most common treatment for many stages of colorectal cancer. Chemotherapy,   radiation , targeted therapy , radiofrequency ablation , and cryosurgery are other treatments that may be used to treat colorectal cancer, depending on the stage.

Because of an increased risk of recurrence, differences in anatomy, and poorer prognosis , the treatment of rectal cancer may differ from that of colon cancer. Although surgery remains a common type of treatment for local and locally advanced rectal cancer, people with some stages may be treated with radiation, chemotherapy, and/or targeted therapy with or without surgery.

In addition to these standard treatments for rectal cancer, researchers continue to study both new treatments, such as immunotherapies, and new combinations of existing treatments in clinical trials.

One trial is comparing a standard treatment (chemoradiation followed by combination chemotherapy) with chemoradiation followed by combination chemotherapy that includes an additional chemotherapy drug.  The goal is to find out whether the additional chemotherapy drug may increase the likelihood of the cancer responding and possibly avoid the need for surgery. 

Immunotherapy for patients with Lynch syndrome or MSI-H colorectal cancer

Approximately 5% of colorectal cancer cases are due to Lynch syndrome , an inherited DNA repair disorder . People with this disorder have an increased risk of developing colorectal cancer, typically before they reach the age of 50. Lynch syndrome colorectal cancer tumors have many mutations, which may make them more susceptible to immunotherapies.

A genetic feature known as  microsatellite instability-high (MSI-H)  is seen in about 15% of patients with stages II and III colorectal cancer and about 5% with stage IV. MSI-H means that there are mistakes in the way the DNA is copied in cancer cells, which can make them grow out of control.

The immune checkpoint inhibitors nivolumab (Opdivo) , ipilimumab (Yervoy) , and pembrolizumab (Keytruda) have all been approved for the treatment of metastatic colorectal cancer in patients with Lynch syndrome and in patients with MSI-H cancers. 

The NCI-sponsored  COMMIT study is testing the addition of atezolizumab (Tecentriq)  to the combination of chemotherapy and the targeted therapy  bevacizumab (Avastin) , for treating patients that have defective DNA mismatch repair. The hope is that combining drugs that work in different ways will improve treatment results in patients with colorectal cancer.

Another NCI-sponsored trial is studying whether atezolizumab will improve outcomes in people with earlier-stage disease (specifically, stage III colon cancer) that is deficient in DNA mismatch repair. This trial will compare combination chemotherapy with or without atezolizumab.

For people with locally advanced rectal cancer who have MSI-H cancer, one trial is studying the effects of nivolumab and ipilimumab when given together with short-course radiation therapy . 

Combining immunotherapy with other treatments for patients without Lynch syndrome

Immune checkpoint inhibitors have been less effective in colorectal cancer patients without Lynch syndrome and whose cancers don't have mismatch repair deficiency . Scientists are currently testing various agents, such as chemotherapy drugs, targeted therapies and viruses, in combination with immune-based therapy to determine whether combining treatments would be effective in killing cancer cells.

Using targeted therapies for metastatic colorectal cancer

Using targeted therapies against genetic mutations that may drive tumor growth is another key area of research for metastatic colorectal cancer. The goal is to find agents that can block the activity of the abnormal proteins produced by these mutations. For example:

• The drug encorafenib (Braftovi ), which targets the BRAF protein, is approved for the treatment of some patients with colorectal cancer . This drug is used in combination with cetuximab (Erbitux) in adults with metastatic colorectal cancer whose tumors have a certain mutation in the BRAF gene and who have already undergone treatment.
• An NCI-supported trial showed that colorectal cancer that contains mutations in the BRAF gene responds to treatment with the drug vemurafenib (Zelboraf) in combination with cetuximab and irinotecan (Camptosar) . Vermurafentib targets mutant B-Raf proteins when combined with these two drugs.
• The NCI-sponsored SOLARIS trial is testing the addition of  vitamin D3 to the combination of chemotherapy and bevacizumab  for treating patients with metastatic colorectal cancer. 
• In January 2023, the Food and Drug Administration (FDA) approved the combination of two targeted drugs, tucatinib (Tukysa) and trastuzumab (Herceptin) for people with advanced colorectal cancer that produces an excess amount of a protein called HER2. (3% or less of people with advanced colorectal cancer have tumors that overexpress this protein.) In the clinical trial that led to the approval, called MOUNTAINEER, more than one third of people who received the drug combination had their tumors shrink or disappear. For another third, tumors stopped growing for some time.

Testing liquid biopsies

Liquid biopsies are a promising new approach being explored to detect, analyze, and track DNA, cells, and other substances shed from tumors into bodily fluids, such as blood and urine. Scientists are testing this method to detect colorectal cancer early, measure treatment responses, identify treatment resistance, and monitor for disease recurrence.

One example is the COBRA trial, which found that testing blood for fragments of genetic material (DNA) shed by tumors , known as circulating tumor DNA (ctDNA), could identify patients with stage IIA colon cancer who might benefit from additional treatment with chemotherapy after surgery.

An ongoing trial is studying ctDNA in people with stage II or III colon cancer. The goal is to determine whether and what type of chemotherapy will benefit patients who have had surgery for their colon cancer based on the presence or absence of ctDNA. 

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and world, are seeking ways to address colorectal cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s research efforts for colorectal cancer.

• The NCI-supported  genetic study, ENLACE, aims to learn more about colorectal cancer in people of Hispanic and Latino descent , with the ultimate goal of improving treatments for this population group. To achieve this, scientists are also testing ways to engage more people from this group in cancer research.
• The Population-based Research to Optimize the Screening PRocess (PROSPR) is an NCI-supported network conducting research to better understand how to improve the entire cancer screening process (recruitment, screening, diagnosis, referral for treatment) for lung, colorectal, and cervical cancer in community healthcare settings.
• Accelerating Colorectal Cancer Screening and Follow-Up Through Implementation Science (ACCIS) is intended to promote research in colorectal cancer screening, follow-up, referral-to-care and best practices for how multilevel interventions can be scaled-up in regions of the United States where screening rates are below national standards.
• Approaches to Identify and Care for Individuals with Inherited Cancer Syndromes are studies designed to increase screening, prevention, and early treatment of people at high risk of cancer due to an inherited genetic susceptibility .
• The NCI-funded Colon Cancer Family Registry (CCFR)  has established an international cohort of thousands of colorectal cancer patients, their relatives, and individuals at increased risk of colorectal and other cancers. Over 10,000 families from the United States, Canada, Australia, and New Zealand have been registered. The database includes more than 2,000 individuals with Lynch syndrome, from 781 families. 
• The goal of the Screen to Save Initiative , funded by NCI’s Center to Reduce Cancer Health Disparities , is to increase colorectal cancer screening in areas that need it most. Through community health educators, the program provides education and outreach to increase access to resources for those who may be affected by colorectal cancer.
• Dissemination of a Colorectal Cancer Screening Program Across American Indian Communities in the Southern Plains and Southwest United States is an effort to increase the use of colorectal cancer screening tests in American Indians. This project supports research on system-level changes and culturally appropriate media to promote screening, with the goal of closing the gap in colorectal cancer outcomes between the American Indian population and the general US population.
• NCI's  Gastrointestinal (GI) SPOREs focus on translational research in the gastrointestinal system. Currently, GI SPOREs focus on cancers of the colon, rectum, esophagus, liver, gastrointestinal stromal tumors (GIST), and pancreas, which account for the majority of new diagnoses.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for colorectal cancer screening , to prevent  colon  and  rectal cancer , and treatment for colon cancer and rectal cancer. 

Colorectal Cancer Research Results

The following are some of our latest news articles on colorectal cancer research:

• ctDNA May Guide Who Needs Chemo After Colorectal Cancer Surgery
• ENLACE Study Explores Colorectal Cancer in Hispanic and Latino People
• Is AI Ready to Play a Leading Role in Colorectal Cancer Screening?
• Some People with Rectal Cancer Can Skip Radiation Before Surgery
• How Fatty Liver Disease Helps Cancer Thrive in the Liver
• Study Identifies Potential Warning Signs of Colorectal Cancer in Younger Adults

View the full list of Colorectal Cancer Research Results and Study Updates .

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Colorectal cancer articles from across Nature Portfolio

Colorectal cancer, also known as bowel cancer, is a cancer formed by uncontrolled cell growth in the colon or rectum (parts of the large intestine), or in the appendix. Genetic analysis shows that colon and rectal tumours are genetically the same cancer.

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• Hideyuki Masui
• Kenji Kawada
• Kazutaka Obama

Mitochondrial function and gastrointestinal diseases

Mitochondria of the intestinal epithelium are vital in intestinal health and disease. This Review provides a comprehensive overview of intestinal epithelial cell mitochondrial dysfunction in inflammatory bowel diseases and colorectal cancer and discusses mitochondrial-targeted therapeutics for these diseases.

• Parsa S. Haque
• Neeraj Kapur
• Arianne L. Theiss

HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis

• Chaoqun Liu

News and Comment

Too much of a good thing

Dias et al. have shown that intentional further activation of oncogenic signalling rather than its inhibition represents an alternative strategy leading to colorectal cancer cell death with tumour suppressive acquired resistance.

Comment on: “Neoadjuvant chemotherapy is noninferior to chemoradiotherapy for early-onset locally advanced rectal cancer in the FOWARC trial”

• Letian Qiao
• Qiumin Yang

A crucial Fusobacterium nucleatum clade in colorectal cancer

• Katrina Ray

Programming immune escape

In a recent study published in Nature , Goto et al. explore mechanisms of immune evasion in early colorectal cancers and adenomas and identify SOX17 to be crucial for immune escape through suppression of interferon-γ signalling.

• Daniela Senft

Enabling comparative gene regulatory network analysis on single-cell data with SCORPION

We present SCORPION, a computational tool to model gene regulatory networks based on single-cell transcriptomic data and prior knowledge of gene regulation. SCORPION networks can be modeled for specific cell types in individual samples, and are therefore suitable for conducting comparisons between experimental groups.

Live bacterial therapeutics for detection and treatment of colorectal cancer

Live microorganisms can be manipulated and engineered for colorectal cancer detection and treatment through methods such as faecal microbiota transplantation, native bacteria engineering and synthetic circuit engineering. Although promising, substantial effort is required to translate these approaches for clinical use.

• Joanna Zhang
• Amir Zarrinpar

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