Global BulletinAll NewsFDA Approval AlertWomen in Oncology
Expert InterviewsAround the PracticeBetween the LinesFace OffFrom All AnglesMeeting of the MindsOncViewPodcastsTraining AcademyTreatment Algorithms with the Oncology Brothers
Conferences
All JournalsEditorial BoardFor AuthorsYear in Review
Frontline ForumSatellite Sessions
CME/CE
Awareness MonthInteractive ToolsNurse Practitioners/Physician's AssistantsPartnersSponsoredSponsored Media
Career CenterSubscribe
Adverse Effects
Brain Cancer
Breast CancerBreast CancerBreast Cancer
Gastrointestinal CancerGastrointestinal CancerGastrointestinal CancerGastrointestinal CancerGastrointestinal CancerGastrointestinal Cancer
Genitourinary CancersGenitourinary CancersGenitourinary CancersGenitourinary Cancers
Gynecologic CancersGynecologic CancersGynecologic CancersGynecologic Cancers
Head & Neck Cancer
Hematologic OncologyHematologic OncologyHematologic OncologyHematologic Oncology
InfectionInfection
Leukemia
Lung CancerLung CancerLung Cancer
Lymphoma
Neuroendocrine Tumors
Oncology
Pediatric Cancers
Radiation Oncology
Sarcoma
Screening
Skin Cancer & Melanoma
Surgery
Thyroid Cancer
Spotlight -
  • Radiation Oncology
  • Surgery
Adverse Effects
Brain Cancer
Breast CancerBreast CancerBreast Cancer
Gastrointestinal CancerGastrointestinal CancerGastrointestinal CancerGastrointestinal CancerGastrointestinal CancerGastrointestinal Cancer
Genitourinary CancersGenitourinary CancersGenitourinary CancersGenitourinary Cancers
Gynecologic CancersGynecologic CancersGynecologic CancersGynecologic Cancers
Head & Neck Cancer
Hematologic OncologyHematologic OncologyHematologic OncologyHematologic Oncology
InfectionInfection
Leukemia
Lung CancerLung CancerLung Cancer
Lymphoma
Neuroendocrine Tumors
Oncology
Pediatric Cancers
Radiation Oncology
Sarcoma
Screening
Skin Cancer & Melanoma
Surgery
Thyroid Cancer
    • Conferences
    • CME/CE
    • Career Center
    • Subscribe
Advertisement

PROSPECT: A Study Whose Time Is Past

July 28, 2023
By Howard S. Hochster, MD
Publication
Article
OncologyONCOLOGY Vol 37, Issue 7
Volume 37
Issue 7
Pages: 273

Co-editor-in-Chief Howard S. Hochster, MD, writes about the past and present of the phase 2/3 PROSPECT trial.

First of all, kudos to Deb Schrag, MD, MPH, and all the investigators of the phase 2/3 PROSPECT trial (NCT01515787) for achieving and completing this landmark study.1 In appreciating its significance, it is helpful to turn back the hands of time to the 1980s. At this time the Gastrointestinal Tumor Study Group performed a 4-arm randomized study in adjuvant therapy of rectal cancer, showing for the first time that both radiation and chemotherapy were better than surgery alone but that the combination of both had the best outcome.2 This study set the stage for an era of surgery, followed by adjuvant chemotherapy and radiation, with radiation sandwiched in the middle 2 months of the 6-month adjuvant program. We also note that, at this time, the standard 5-fluorouracil (5FU)-leucovorin treatment was the “Mayo regimen” with 5 days of bolus of 5FU.

The next major advance in rectal cancer therapy came with the concept of preoperative chemoradiation therapy. Over time, physicians realized that a major long-term toxicity of the postoperative approach described above was many patients having the late adverse effects (AEs) of significant rectal strictures. These patients, after being cured, lived a life with bowel dysfunction. Many of them eventually required colostomy to function relatively normally at work and in daily activities.

This led to the German randomized trial of preoperative chemoradiation (with adjuvant chemotherapy) vs the standard of care, postoperative therapy, whose results demonstrated better local control and equal survival but, importantly, fewer long-term AEs.3 This changed the rectal cancer paradigm to preoperative chemoradiation followed by surgery, followed by 4 to 6 months of adjuvant chemotherapy. Additionally, at the same time, emerging data on rectal surgery suggested that local recurrence in the pelvis could be reduced using a more technically complete surgical approach of total mesorectal excision (TME). This approach, using sharp dissection along the natural tissue planes, and keeping the mesorectal fascia intact, was superior to the prior technique of blunt dissection, using the surgeon’s fingers to mobilize the rectum. With the use of TME, the need for radiation for local control was called into question once more.

It is in this context that the PROSPECT trial was framed about 12 years ago (opening to accrual in 2012), asking the question: Does every patient need chemoradiation after neoadjuvant chemotherapy, in the setting of better surgery and good response to chemotherapy? This was a groundbreaking study, attempting to show that we are overtreating some patients who do not require it. In this study, the “neoadjuvant” therapy functions like a biomarker test for responsive patients with 20% or greater shrinkage as marking a good prognosis with chemotherapy and not needing radiation.

The PROSPECT study unequivocally showed, using a large noninferiority design of 1200 patients, that radiation is not always necessary. For patients with radiographic T2-3 and/or N1 rectal cancers, those who respond to the “chemotherapy test” with more than 20% shrinkage have the same outcome for local recurrence and survival when treated with chemotherapy and surgery as those who received the standard chemoradiation followed by surgery and adjuvant chemotherapy––as proved by noninferior outcomes. We offer a huge “bravo!” to those investigators and patients who participated in the study, and to study leadership in showing we can reduce the amount of toxic therapy.

More recently, progress in the treatment of rectal cancer is focused on the total neoadjuvant therapy (TNT) approach. In this treatment paradigm, chemotherapy and chemoradiation are moved up front and surgery is performed last, and only if necessary. Most importantly, this approach maximizes the number of patients with a clinical complete response (CR) and pathologic complete response (pCR) who may be spared surgical resection. This is particularly important for low-lying cancers, which would otherwise require an abdominoperineal resection. The nonoperative management (NOM) approach was first documented by Angelita Habr-Gama, MD, PhD, in Brazil.

Most recently, findings from the phase 2 OPRA trial (NCT02008656), led by Julio Garcia-Aguilar, MD, PhD, at Memorial Sloan Kettering Cancer Center, showed a high NOM rate and an improved pCR status for patients treated with chemoradiation followed by chemotherapy, compared with the opposite sequence.4 The TNT approach is now favored by the US community in an attempt to spare patients from rectal surgery.

In many respects, the PROSPECT trial has been superseded by advances in therapy for rectal cancer, particularly with the TNT and NOM approaches that eliminate some surgeries rather than radiation. Nonetheless, the PROSPECT trial was a massive undertaking with a 1200-patient sample size. Such a large sample size for a rectal cancer trial has never been achieved in the United States previously. With this noninferiority approach, we can accept the fact that it is safe to treat responding patients without rectal radiation using the chemotherapy-first approach. However, in 2023 the field has moved on from this to the use of TNT and NOM. We do note, though, that there are no large comparative trials to demonstrate the equal efficacy of TNT vs conventional therapy as of this date. We again express our gratitude to the PROSPECT leadership and investigators for showing us an undisputed path to reducing debilitating cancer treatments by adapting treatment to response.

References

  1. Schrag D, Shi Q, Weiser MR, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med. Published online June 4, 2023. doi:10.1056/NEJMoa2303269
  2. Gastrointestinal Tumor Study Group. Prolongation of the disease-free interval in surgically treated rectal carcinoma. N Engl J Med. 1985;312(23):1465-1472. doi:10.1056/NEJM198506063122301
  3. Sauer R, Becker H, Hohenberger W, et al; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-1740. doi:10.1056/NEJMoa040694
  4. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004;240(4):711-718. doi:10.1097/01.sla.0000141194.27992.32
  5. Garcia-Aguilar J, Patil S, Gollub MJ, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(23):2546-2556. doi:10.1200/JCO.22.00032
Download Issue PDFDownload PDF
Articles in this issue

Recap: Available Treatment Options in Transplant-Eligible Multiple Myeloma
Recap: Available Treatment Options in Transplant-Eligible Multiple Myeloma
T-DXd Has Revolutionized the Standard of Care in Breast Cancer
T-DXd Has Revolutionized the Standard of Care in Breast Cancer
PROSPECT: A Study Whose Time Is Past
PROSPECT: A Study Whose Time Is Past
Erdheim-Chester Disease: A Case Report of BRAF V600E–Negative, MAP2K1-Positive ECD Diagnosed by Blood Next-Generation Sequencing Assay and a Brief Literature Review
Erdheim-Chester Disease: A Case Report of BRAF V600E–Negative, MAP2K1-Positive ECD Diagnosed by Blood Next-Generation Sequencing Assay and a Brief Literature Review
De-Escalation Treatment for Human Papillomavirus–Related Oropharyngeal Cancer: Questions for Practical Consideration
De-Escalation Treatment for Human Papillomavirus–Related Oropharyngeal Cancer: Questions for Practical Consideration
Recent Videos
Testing a patient’s genetics may influence decisions such as using longer courses of radiotherapy, says Rachit Kumar, MD.
Spatial transcriptomics and multiplex immunohistochemistry from samples may elucidate outcomes for patients who undergo surgical care for cancer.
Future work may focus on optimizing symptom management associated with percutaneous transesophageal gastrostomy placement in malignant bowel obstructions.
Post-operative length of stay ranged from 4 to 9 days for patients who underwent percutaneous transesophageal gastrostomy for malignant bowel obstructions.
Treatment with KRAS inhibitors may help mitigate a common driver of genetic alteration across a majority of pancreatic cancers.
Various methods of communication ensure that members from radiation oncology, pathology, and other departments are on the same page regarding treatment.
Updated results from the BREAKWATER study seemed to be most impactful to the CRC space, according to Michael J. Pishvaian, MD, PhD.
Related Content
Advertisement

The safety profile of TFOX was consistent with data reported in previous studies, and no new safety signals were identified.

TFOX Regimen Enhances Efficacy vs FOLFOX in HER2-Negative Gastric Cancer

Roman Fabbricatore
May 11th 2025
Article

The safety profile of TFOX was consistent with data reported in previous studies, and no new safety signals were identified.


The approval of sotorasib plus panitumumab is a “welcome step” in KRAS G12C-mutated colorectal cancer, according to Marwan G. Fakih, MD.

Sotorasib Combo Approval May Address Novel Therapy Need in KRAS G12C+ CRC

Marwan G. Fakih, MD
February 24th 2025
Podcast

The approval of sotorasib plus panitumumab is a “welcome step” in KRAS G12C-mutated colorectal cancer, according to Marwan G. Fakih, MD.


"[G]iven the improvements in compliance and tolerability of the de-escalated regimen in older patients, with preserved early cancer outcomes, this reduced-dose regimen could be considered a new treatment option for [patients who are] frailer [and] not fit for standard-dose chemoradiotherapy," according to the study authors.

Chemoradiation Shows Responses Across Dose Levels in Anal Cancer

Russ Conroy
May 9th 2025
Article

Phase 2 data indicate that reduced-dose chemoradiotherapy may be tolerable among patients with early-stage anal cancer.


Kelley A. Rone, DNP, RN, AGNP-c, provides perspective on approaching end-of-life conversations with patients with GI cancers.

Educating Patients and Clinicians on End-of-Life Care and Discussions

Kelley A. Rone, DNP, RN, AGNP-c
November 11th 2024
Podcast

Kelley A. Rone, DNP, RN, AGNP-c, provides perspective on approaching end-of-life conversations with patients with GI cancers.


Phase 2 Actuate-1801 part 3B trial results evaluating elraglusib with GnP in metastatic PDAC will be presented at the 2025 ASCO Annual Meeting.

Elraglusib Combo Demonstrates OS Benefit in Metastatic Pancreatic Cancer

Roman Fabbricatore
May 8th 2025
Article

Phase 2 Actuate-1801 part 3B trial results evaluating elraglusib with GnP in metastatic PDAC will be presented at the 2025 ASCO Annual Meeting.


Pathological complete response was higher among patients with ERBB2–positive gastric cancer or GEJ adenocarcinoma treated with atezolizumab vs without.

Atezolizumab/Trastuzumab Plus Chemotherapy Shows Efficacy in Gastric Cancer

Roman Fabbricatore
May 7th 2025
Article

Pathological complete response was higher among patients with ERBB2–positive gastric cancer or GEJ adenocarcinoma treated with atezolizumab vs without.

Related Content
Advertisement

The safety profile of TFOX was consistent with data reported in previous studies, and no new safety signals were identified.

TFOX Regimen Enhances Efficacy vs FOLFOX in HER2-Negative Gastric Cancer

Roman Fabbricatore
May 11th 2025
Article

The safety profile of TFOX was consistent with data reported in previous studies, and no new safety signals were identified.


The approval of sotorasib plus panitumumab is a “welcome step” in KRAS G12C-mutated colorectal cancer, according to Marwan G. Fakih, MD.

Sotorasib Combo Approval May Address Novel Therapy Need in KRAS G12C+ CRC

Marwan G. Fakih, MD
February 24th 2025
Podcast

The approval of sotorasib plus panitumumab is a “welcome step” in KRAS G12C-mutated colorectal cancer, according to Marwan G. Fakih, MD.


"[G]iven the improvements in compliance and tolerability of the de-escalated regimen in older patients, with preserved early cancer outcomes, this reduced-dose regimen could be considered a new treatment option for [patients who are] frailer [and] not fit for standard-dose chemoradiotherapy," according to the study authors.

Chemoradiation Shows Responses Across Dose Levels in Anal Cancer

Russ Conroy
May 9th 2025
Article

Phase 2 data indicate that reduced-dose chemoradiotherapy may be tolerable among patients with early-stage anal cancer.


Kelley A. Rone, DNP, RN, AGNP-c, provides perspective on approaching end-of-life conversations with patients with GI cancers.

Educating Patients and Clinicians on End-of-Life Care and Discussions

Kelley A. Rone, DNP, RN, AGNP-c
November 11th 2024
Podcast

Kelley A. Rone, DNP, RN, AGNP-c, provides perspective on approaching end-of-life conversations with patients with GI cancers.


Phase 2 Actuate-1801 part 3B trial results evaluating elraglusib with GnP in metastatic PDAC will be presented at the 2025 ASCO Annual Meeting.

Elraglusib Combo Demonstrates OS Benefit in Metastatic Pancreatic Cancer

Roman Fabbricatore
May 8th 2025
Article

Phase 2 Actuate-1801 part 3B trial results evaluating elraglusib with GnP in metastatic PDAC will be presented at the 2025 ASCO Annual Meeting.


Pathological complete response was higher among patients with ERBB2–positive gastric cancer or GEJ adenocarcinoma treated with atezolizumab vs without.

Atezolizumab/Trastuzumab Plus Chemotherapy Shows Efficacy in Gastric Cancer

Roman Fabbricatore
May 7th 2025
Article

Pathological complete response was higher among patients with ERBB2–positive gastric cancer or GEJ adenocarcinoma treated with atezolizumab vs without.

Advertisement
About
Advertise
CureToday.com
OncLive.com
OncNursingNews.com
TargetedOnc.com
Editorial
Contact
Terms and Conditions
Privacy
Do Not Sell My Personal Information
Contact Info

2 Commerce Drive
Cranbury, NJ 08512

609-716-7777

© 2025 MJH Life Sciences

All rights reserved.