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Results for “Pathologic Complete Response”

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PubMed1990

The potential of primary cytoreductive surgery in patients with FIGO stages III and IV ovarian carcinoma.

The present study included 40 patients with advanced ovarian carcinoma who underwent surgery and combination chemotherapy with cisplatin or carboplatin at the Department of Gynecology and Obstetrics of the University of Pisa. All the 20 optimally cytoreduced (residual disease lower than 2 cm) patients were clinically free of disease after the sixth course of chemotherapy; second-look laparotomy showed a pathological complete response (PCR) in 16 of them (80%). The 5-year actuarial progression- free and overall survival rates of this group of patients were 44.0% and 82.2% respectively. Among the 20 patients with residual disease greater than 2 cm after the first laparotomy, a clinical complete response was obtained in 3 (15%) and a clinical partial response in 12 (60%); a PCR was achieved in only 1 (5%) of them. The 5-year actuarial progression- free and overall survival rates of this group of patients were 0% and 14.2% respectively. The present paper confirms that surgery plays a major role in the treatment of ovarian carcinoma. Aggressive surgical removal with optimal tumor reduction can produce a favourable effect on patients survival time, since there is an inverse relationship between the volume of residual disease after the first laparotomy and the likelihood of response to chemotherapy.

Antineoplastic Agents↗

PubMedDate not supplied

CA-125 monitoring in the management of ovarian cancer.

In 100 ovarian cancer patients serum CA-125 was monitored during treatment and follow-up to verify the prognostic value of its pre-surgery marker level and the usefulness of the test for disease monitoring. A low pre-operative CA-125 was not associated with improved survival or progression-free survival. A significant survival advantage was evident for patients in whom the marker had decreased during treatment, compared to patients in whom the antigen remained unchanged or increased. In 40 patients CA-125 was measured before second look laparotomy: the marker was negative in 100% of patients in, pathological complete response and in 53.5% of patients with residual disease at second look. A marker increase was evident in 32 of 41 patients with either progressive or recurrent disease, and in 17 patients the CA-125 increase was documented from 1 to 9 months before clinical evidence of progression. The pre-operative level of CA-125 did not appear to be of prognostic value. However, the monitoring of CA-125 during treatment and follow-up can provide a reliable method of assessing response and prognosis. CA-125 monitoring is particularly useful for early detection of recurrence.

Adult↗

PubMed1990

Multidisciplinary therapy for esophageal cancer.

The use of combined-modality therapy programs, including systemic chemotherapy plus radiotherapy, are being studied intensively, since pilot trials have consistently shown improvement in 1- or 2-year survival statistics compared with historic controls. The mechanisms of interaction of the most popular chemotherapeutic drugs (5-FU, mitomycin C, and cisplatin) when used with irradiation are not fully understood. Further clinical work will be necessary to optimize the best combination of agents, their dose levels, and method and schedules of administration. Pathologic complete responses ranging from 37 to 45% have been reported in some series using preoperative chemoradiation and may translate into better survival rates for some patient subgroups. Several randomized multiinstitutional trials are underway to assess the utility of chemoradiation in comparison to radiotherapy alone in order to confirm these initial encouraging results. From these data, it would be prudent to consider the use of 5-FU continuous infusion treatment with or without other chemotherapeutic agents in conjunction with conventionally fractionated irradiation. Radiotherapy should be given in a continuous fractionated course rather than given as a split course. With these guidelines, the acute complications and late complications seem to be acceptable and not increased over those expected with radiotherapy alone.

Combined Modality Therapy↗

PubMed1989

[Prognosis in ovarian cancer as a function of the results of the second-look laparatomy].

Second-look laparotomy (SLL) was performed after chemotherapy in 106 patients with epithelial ovarian cancer. Thirteen were stage I and II and 93 stage III and IV. Seventy-eight patients received cisplatin-based regimens. Median follow-up was 60 months. Negative SLL was found in 32 patients who had a 5-year survival rate of 43.4% after SLO. Microscopy residual disease was present in 9 patients whose 5-year survival rate was 25%. Maximum residual tumor of 2 cm or less was found in 13 patients with 5-year survival rate of 30%. Residual tumor larger than 2 cm after secondary cytoreduction was present in 21 patients, their 3-year survival rate was 18.3%. Eighteen patients with bulky residual disease who did not have cytoreduction were all dead within 17 months. Patients with initial residual tumor at first laparotomy less than 2 cm had a near significant advantage in survival rate over patients with residual disease greater than 2 cm and stage IV (p = 0.07). Non-responders to initial chemotherapy had a survival rate similar to that of partial-responders. These findings justify discontinuation of conventional systemic chemotherapy for patients showing residual disease after SLL and secondary tumor removal in case of residual tumor at SLL. Therapeutic trials are needed in advanced ovarian cancer testing initial aggressive surgery or early debulking to avoid bulky residual disease and consolidation therapy in patients who achieved complete pathological response or minimal residual intraperitoneal disease.

Adult↗

PubMed1989

Survival after negative second-look laparotomy.

Complete pathological responses, as defined by multiple negative intraperitoneal biopsies at second-look laparotomy, were recorded in 22 of 120 patients with epithelial ovarian cancer. Patients had been previously treated with either high-dose single agent cisplatinum (19) or total abdominal and pelvic irradiation (3). Nine of 21 (43%) evaluable patients developed recurrent disease after 'negative' second-look laparotomy. The median time to relapse was 15 months (3-19) and the median survival after relapse, 4 months (1-6). One patient remains alive with evidence of disease.

Adolescent↗

PubMed1985

Intraperitoneal recombinant alpha-interferon for "salvage" immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study.

Fourteen patients with persistent epithelial ovarian cancer documented at second look laparotomy after combination chemotherapy were treated with 146 cycles of alpha-recombinant interferon (rIFN-alpha 2) administered i.p. The initial dose was 5 X 10(6) units which was escalated weekly to 50 X 10(6) units over 4 weeks and then continued weekly for a total of 16 weeks. Eleven patients underwent surgical reevaluation after therapy which confirmed four pathological complete responses (36%), one partial response (9%), and disease progression in six patients (55%). Five of seven patients (71%) with residual tumor less than 5 mm had a surgically documented response, whereas there was no response in the four patients whose tumors were greater than or equal to 5 mm. Three patients were evaluable for clinical response only: one patient who refused surgery had a complete clinical response with total resolution of ascites; one had stable disease; and one had disease progression. Fever greater than or equal to 38 degrees C was seen in 58%, fever greater than or equal to 39.0 degrees C was seen in 18%, vomiting in 37%, abdominal pain was reported in 22%, and one patient had infectious peritonitis. Peripheral white blood cell counts and i.p. washings were obtained pretreatment and on days 1, 3, and 7 after treatment. While there was no consistent alteration in peripheral white blood cell counts, the numbers of i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood natural killer lymphocyte cytotoxicity values showed considerable variability. Pharmacokinetic studies show that i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. rIFN-alpha 2 i.p. may act by increasing concentrations of drug and augmenting regional host cells in patients with minimal residual ovarian cancer.

Adult↗

PubMed1990

Continuous infusion high-dose leucovorin with 5-fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck.

STUDY OBJECTIVE: To study the activity of continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin (PFL) as induction chemotherapy in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. DESIGN: Nonrandomized, prospective trial. SETTING: A comprehensive cancer center. PATIENTS: Thirty-five patients (4 patients [11%], stage III; 31 patients [89%], stage IV [MO]), all evaluable for response and toxicity. INTERVENTIONS: Two to three cycles of PFL before definitive, local-regional therapy (surgery and radiation therapy or radiation therapy alone). Chemotherapy included continuous intravenous infusion of cisplatin (25 mg/m2 body surface area daily, days 1 through 5); 5-fluorouracil (800 mg/m2 body surface area daily, days 2 through 6); and leucovorin (500 mg/m2 body surface area daily, days 1 through 6) administered once every 28 days. Pathologic response was evaluated by surgical resection or biopsy. Serum-reduced folates were measured before and 18 hours after the initiation of chemotherapy. RESULTS: A clinical response to PFL was achieved in 28 of 35 (80%) patients: 23 (66%) patients had a complete response (90% CI, 50% to 79%) and 5 (14%) patients, a partial response. A complete response was confirmed pathologically in 14 of 19 (74%) patients. The most common toxicity was mucositis (grade 2 to 3; 94% of patients). Dose reduction for toxicity was necessary in 11 (31%) patients. There were no treatment-related deaths. Serum levels of leucovorin and (6S)5-methyltetrahydrofolate were measured in 7 patients. After 18 hours, the mean leucovorin level (+/- SD) was 34.3 +/- 1.5 mumol/L, of which only 8.0 +/- 0.5% was the active 6S isomer. The mean serum (6S)5-methyltetrahydrofolate was 9.2 +/- 0.6 mumol/L. CONCLUSIONS: Continuous infusion cisplatin, 5-fluorouracil, and high-dose leucovorin is a new and highly active chemotherapy regimen that can achieve clinical and pathologically confirmed complete responses in a substantial proportion of patients with advanced, local-regional squamous cell carcinoma of the head and neck. Further studies are needed to confirm the activity of PFL and to determine its potential impact on local tumor control and disease-free and overall survival.

Adult↗

PubMed1991

Single agent epirubicin in squamous cell cervical cancer. A phase II trial.

Thirty consecutive patients with FIGO stage III-IV, squamous cell uterine cervix cancer were entered in a phase II trial evaluating activity and safety of epirubicin when given at a dose of 80 mg/m2 i.v., every 3 weeks. Two complete responses (including a pathological complete remission) plus 3 partial responses were observed among 27 evaluable patients with a response rate of 18.5% (95% confidence limits = 7.6%-36.4%). The median time to progression and median survival for all treated patients were 3 and 8 months respectively. Treatment was well tolerated. Haematological toxicity was mild. WHO grade 4 toxicity was not observed. The median total cumulative dose of epirubicin was 360 mg/m2 (80-840 mg/m2). Congestive heart failure was not noted. Further studies in cervical cancer with higher doses of epirubicin as single agent or in combination with other nonmyelotoxic drugs are indicated.

Adult↗

PubMedDate not supplied

[Multidisciplinary protocol for the treatment of epidermoid carcinoma of the esophagus: experience from 1985 to 1989].

A phase II study activated in 1985 for the multidisciplinary treatment of squamous cell carcinoma of the esophagus is described. The treatment program included simultaneous neoadjuvant continuous infusion chemotherapy with cisplatinum and 5-fluorouracil, preoperative radiotherapy (46 Gy in 5 weeks) and delayed programmed surgery (or radical irradiation in selected cases). Twenty-one patients with tumor stages I (6), II (10), III (5) entered in the study and 20 patients completed the treatment program. Severe toxicity observed was: esophagitis 100%, bone marrow aplasia 30%, severe weight loss 52%. One patient developed a tracheo-esophageal fistula at the end of radiotherapy. Clinical objective tumor response rate was 85%. Pathologic complete tumor response rate was 47%. Median follow-up of the entire group is 11 months (range 2 + to 49 + months). Ten patients have been alive for more than 12 months; six are still alive without any evidence of disease (from 12 + to 49 + months). It is concluded that the protocol described is feasible, with treatment related severe but reversible toxicities, and able to induce a high rate of tumor response and long term survivors in patients with initial locally advanced tumor stages.

Adult↗

PubMed1992

Cisplatin-containing regimen in advanced or recurrent granulosa cell tumours of the ovary.

The efficacy of combination chemotherapy in advanced or recurrent disease of granulosa cell tumours is still not well defined. Ten patients with advanced or recurrent granulosa cell tumours were treated with cisplatin, adriamycin and cyclophosphamide (CAP). Prior to chemotherapy all patients underwent surgical treatment. No patient received prior hormonochemotherapy or radiotherapy. Five complete responses (three pathologically documented) and one partial response were obtained for a total response rate of 60%. One pathologically-complete responder relapsed after 48 months from the onset of chemotherapy, but responded completely to debulking surgery and radiotherapy and remains well with no evidence of disease 87+ months. Five patients are still alive with no evidence of disease at 10+, 26+, 41+, 46+, 87+ months, 1 is still alive with disease and 4 have died at 20, 22, 28 and 60 months despite further treatment. Additional cooperative clinical trials are required to determine the exact efficacy of cisplatin chemotherapy in granulosa cell tumours.

Adult↗

PubMed1992

Treatment of locoregional esophageal cancer.

Since the mid 1970s combined-modality treatment has been investigated for locoregional cancer of the esophagus. Single-institution pilot studies of preoperative cisplatin-based chemotherapy have shown that 40% to 60% of patients with squamous cell carcinoma achieve a partial response, while an occasional patient has a pathologically documented complete response (CR). Two randomized trials involving small numbers of patients have not confirmed the survival benefit for preoperative chemotherapy that some pilot studies suggested. A large, multicenter intergroup trial is in progress, comparing preoperative and postoperative cisplatin/5-fluorouracil chemotherapy with immediate surgery, and includes both squamous cell carcinoma and adenocarcinoma histologies. Preoperative chemoradiotherapy programs have used survival and pathologic CR as end points. Single-institution and multicenter pilot studies have consistently reported pathologic CR in 25% to 30% of patients. Median survivals have varied from 12 to 29 months. The results from multicenter pilot trials are at the lower end of this range, with more encouraging results coming from single institutions. One randomized trial in progress compares a 3-week intensive cisplatin/vinblastine/5-fluorouracil and concurrent radiotherapy regimen followed by surgery with immediate surgery. No completed comparative trials have been published. Chemoradiotherapy without surgery is a more recent approach stimulated both by the poor survival rates with primary surgery and by its associated morbidity and mortality. The results of the intergroup randomized trial of concurrent cisplatin 5-fluorouracil/radiotherapy versus radiotherapy alone have demonstrated a role for chemotherapy. Median survival and 12- and 24-month survival improved significantly with the combined-modality treatment. This treatment program is now recommended for patients with locoregional disease who are not candidates for surgery. The optimal management of patients with esophageal cancer is still unknown. Accurate methods to stage patients clinically and to identify prognostic factors are needed. The randomized trials in progress evaluating preoperative and postoperative chemotherapy and preoperative chemoradiotherapy are essential to move forward with improved treatment strategies.

Antineoplastic Agents↗

PubMedDate not supplied

Intraperitoneal chemotherapy with carboplatin and interferon alpha in the treatment of relapsed ovarian cancer: a pilot study.

In ovarian cancer patients intraperitoneal chemotherapy confers pharmacokinetic advantages and appears an attractive way to improve the efficacy of certain antineoplastic agents. Intraperitoneal carboplatin and interferon alpha have been separately evaluated in ovarian cancer "with promising results". We report a phase I-II pilot trial of intraperitoneal carboplatin 400 mg/sqm plus interferon alpha 25 x 10(6) U q 28 d in 16 patients (pts) previously treated with intravenous cisplatin based chemotherapy. All the patients had relapsed (11 pts) or refractory (5 pts) disease; residual tumors were less than 2 cm in 10 pts and greater than 2 cm in 6 pts. Local and general toxicities were moderate, with neither WHO grade 4, nor neurotoxicity and ototoxicity. Myelotoxicity was the most frequent side effect. Among 14 evaluable pts, objective responses were observed in 6 pts (42.8%) including 3 pts with pathologically confirmed complete response (21.4%); six more pts presented prolonged disease-free survival. Response occurred in both categories of pts with greater than or less than 2 cm residual disease, also in pts refractory to prior intravenous cisplatin. The proper role of intraperitoneal treatment cannot be exactly defined without large randomized trials designed to compare intraperitoneal to intravenous drug administrations.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Preoperative simultaneously administered cis-platinum plus radiation therapy for advanced squamous cell carcinoma of the head and neck.

Synchronously administered cis-platinum (cis-DDP) and radiation therapy have been used to treat unresectable squamous cell carcinomas of the head and neck. The purpose of this study was to evaluate the efficacy and tolerance of preoperative adjuvant cis-DDP plus radiation therapy in operable stage III and IV head and neck cancers. Radiation therapy (4,500 rad) was delivered in 180-rad daily fractions. Cis-DDP (20 mg/M2) was given before radiotherapy on days 1-4 and 21-24. Eighteen patients began therapy; 16 completed the combined regimen. Toxicity included stomatitis and WBC below 2,500/mm3. One patient died from therapy of a cerebrovascular accident. Sixteen patients (89%) achieved a complete or partial response to therapy. Complete responses were observed in 13 of 18 primary tumors (72%), and in all three patients with cervical lymphadenopathy. Complete responses were noted for lesions of the nasopharynx, oral cavity, pharynx, hypopharynx, and larynx, for all histologic grades of squamous cell carcinoma. Twelve patients underwent curative surgery. Site-related morbidity occurred in two patients (15%) and a third patient developed postoperative pneumonia. Five of 10 resected primary tumors with preoperative complete responses were pathologically negative for tumor. Concurrent bolus cis-DDP and radiation therapy are well-tolerated and result in impressive tumor reduction. Morbidity after subsequent curative surgery is low, and histologic complete responses are frequent.(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Squamous Cell↗

PubMed1992

Preoperative systemic chemotherapy followed by adjuvant postoperative intraperitoneal therapy for gastric cancer: a University of Southern California pilot program.

PURPOSE: A clinical trial for patients with gastric cancer amenable to curative resection was undertaken to determine feasibility and response to preoperative systemic chemotherapy followed by postoperative intraperitoneal (IP) chemotherapy. METHODS AND MATERIALS: Thirty-eight patients with resectable gastric tumor received two cycles of protracted intravenous (IV)-infusion fluorouracil (5FU), 200 mg/m2/d, for 3 weeks with weekly IV leucovorin 20 mg/m2 and IV cisplatin 100 mg/m2 days 1 and 29. Resection of the gastric tumor followed within 3 weeks of completion of systemic chemotherapy. Those who had all visible tumor removed with clear margins received two cycles of IP floxuridine 3,000 mg (total dose) per day for 3 days and IP cisplatin 200 mg/m2 with IV sodium thiosulfate on the fourth day of IP therapy. RESULTS: Thirty-seven of 38 patients (97%) received two cycles of systemic chemotherapy. Thirty-five of 38 patients (92%) underwent laparotomy for gastric tumor resection. Thirty-three patients (87%) had gastric resections performed; 29 (76%) had all visible tumor removed with microscopically negative margins. No operative mortality was encountered. Twenty-six patients (68%) received IP treatment. IV neoadjuvant treatment was well tolerated and resulted in 68% of the patients reporting improvement in abdominal pain, 45% objective remissions by computed tomography (CT), 38% objective remissions by gastroscopy and biopsy, and 8% had complete surgical pathologic response. Neutropenic sepsis during the IP treatment phase contributed to the only treatment-related death. Four of 29 completely resected patients (14%) have had tumor recurrence. The median follow-up time of patients remaining alive is now 19 months. The median survival for 38 patients entered onto this protocol has not been reached at 17+ months. CONCLUSION: This novel approach to the treatment of adenocarcinoma of the stomach is feasible. The neoadjuvant systemic therapy results in significant primary tumor regression. The determination of whether systemic or IP components of the program contribute to decreased recurrence or increased survival awaits a prospectively randomized clinical trial.

Adenocarcinoma↗

PubMed1989

Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma.

A total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18-36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity.

Altretamine↗

PubMed1988

Clinical relevance of various microscopical features of the second-look specimen in advanced ovarian cancer.

The second-look specimens of 70 patients with advanced ovarian cancer (FIGO 2B, 3, and 4) were reviewed and classified according to four categories: no response to chemotherapy (category a), predominantly histologically viable tumor with some necrotic and/or fibrotic tissue (category b), predominance of fibrosis and recrosis (category c), and no evidence of tumor, i.e., pathologically proven complete response (PCR) (category d). All of the patients in categories a and b had died because of ovarian cancer at the end of the observation period. In category c, 17/25 patients eventually achieved a PCR as established at a third-look procedure. The median survival of 56 months in this group was lower than that of the patients in category d (64 months), although this difference was without statistical significance. These observations underscore the importance of the microscopical features of the second-look specimen for the treatment of advanced ovarian cancer.

Female↗

PubMed1991

Continuous intra-arterial administration of recombinant interleukin-2 in low-stage bladder cancer. A phase IB study.

Toxicity and clinical effects of intra-arterial (IA) continuous infusion of recombinant interleukin-2 (rIL-2) were evaluated in twelve patients with low-stage transitional cell carcinoma (TCC) of the bladder (T1NOMO; G1 to G2). rIL-2 dosages were escalated from 18 x 10(3) to 18 x 10(6) IU/m2/d in four groups of three patients. After two 5-day courses, separated by a 48-hour interval, evaluation of clinical response and transurethral resection (TUR) were carried out. World Health Organization (WHO) Grade 3 toxicity occurred in 2 of 12 patients (hypotension/mental confusion and fever, respectively); all side effects rapidly disappeared after infusion was abandoned. No laboratory toxicity developed in any patient. Two pathologically proven complete responses (CR) were achieved using 18 x 10(4) IU/m2/d, and three partial responses (PR) were achieved using 18 x 10(5) IU/m2/d in two patients and 18 x 10(6) IU/m2/d in one patient, giving an overall response rate of 42%. All objective responses are still ongoing after a mean follow-up time of 23 months (range, 12 to 32 months). Local relapses occurred 3 months after TUR only in two nonresponders.

Adult↗

PubMed2026

Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial.

BACKGROUND: Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. We assessed whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality-of-life harms without compromising oncological outcomes. METHODS: STAR-TREC is an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial in five European countries. Eligible patients were aged 16 years or older in the UK or aged 18 years or older elsewhere, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and rectal adenocarcinoma (≤40 mm staged as mrT1-T3bN0). In phase 2, participants were randomly assigned (1:1:1) to LCCRT-based organ preservation (LCCRT-OP; 50 Gy in 25 fractions plus oral capecitabine 825 mg/m2 twice daily), SCRT-based organ preservation (SCRT-OP; 25 Gy in five fractions), or primary TME. Phase 2 assessed feasibility, with recruitment at months 12 and 24 as the primary endpoint and feasibility thresholds of four or more and six or more randomisations per month, respectively. Phase 3 adopted a partially randomised patient-preference design, allowing participants to choose either organ preservation or TME. Participants that chose organ preservation were randomly assigned (1:1) to receive LCCRT-OP or SCRT-OP using centralised, computer-generated assignment, with stratification by country and MRI T category (≤T3a vs T3b) using minimisation. The phase 3 primary endpoint was organ-preservation 30 months after treatment initiation, defined as absence of TME, stoma, or local recurrence, which was assessed in the modified intention-to-treat population, which included participants in phase 2 and phase 3. After a planned interim analysis of unmasked phase 2 data, the trial steering committee and independent data monitoring committee recommended reporting a 12-month, modified intention-to-treat analysis of implementation outcomes for participants recruited before Aug 8, 2023. This study is registered with ISRCTN (14240288) and is closed. FINDINGS: Between June 14, 2017, and April 8, 2024, 503 participants were enrolled at 37 sites. Phase 2 enrolled 120 participants, with recruitment rates of three and six participants per month at months 12 and 24, respectively. Overall, 12-month TME-free survival was 60% (47 of 78 participants). After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month median TME-free survival not reached [95% CI not reached-not reached] vs 7·6 months [95% CI 6·4-not reached]; hazard ratio [HR] 3·7 [95% CI 1·7-8·0]; posterior probability of superiority >99·5%). The trial steering committee and independent data monitoring committee therefore recommended expanded analysis of 426 participants recruited before Aug 8, 2023: 120 from phase 2 and 306 from phase 3. 17 participants withdrew before treatment, leaving 409 in the modified intention-to-treat population: 163 allocated to LCCRT, 168 to SCRT, and 78 to primary TME. 116 (28%) participants were female and 293 (72%) were male. Among participants who opted for organ preservation, 12-month TME-free survival was 78·5% (95% CI 72·4-85·1) with LCCRT and 60·6% (53·6-68·4) with SCRT (HR 1·90 [95% CI 1·29-2·81]). The most common grade 3-4 serious adverse events were gastrointestinal disorders (four [2%] with LCCRT vs six [4%] with SCRT vs six [8%] with TME) and procedural complications (three [2%] with LCCRT vs five [3%] with SCRT vs five [6%] with TME). One participant allocated to primary TME died after an anastomotic leak. INTERPRETATION: These early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months. Organ-preservation might also reduce treatment-related toxicity compared with primary TME. Longer follow-up is needed for the prespecified 30-month endpoint and definitive functional and oncological outcomes. FUNDING: Cancer Research UK, Stand Up to Cancer, Dutch Cancer Society, Danish Cancer Society, Kom Op Tegen Kanker, Cancerfonden, ALF Region Stockholm, RCC Region Stockholm.

Humans↗