Short-course preoperative radiotherapy combined with chemotherapy, delayed surgery and local hyperthermia for rectal cancer: a phase II study

Abstract

Purpose: The aim of this study was to investigate the feasibility of short-course radiotherapy with oral capecitabine, hyperthermia and delayed surgery for neoadjuvant treatment of rectal cancer.

Methods: Patients with clinically staged T2-3N0-2M0 primary rectal cancer were included. All patients received short-course 25 Gy in 5 Gy fractions radiotherapy with capecitabine, local hyperthermia and metronidazole. Capecitabine 1000 mg/m² twice a day was given on days 1–14. Local hyperthermia, 41–45 °C for 60 min, was performed on days 3–5. Metronidazole 10 g/m² was administered per rectum on days 3 and 5. The time interval to surgery was not less than four weeks after neoadjuvant treatment. The primary end-point was pathological complete response (pCR). Secondary end-points included neoadjuvant treatment toxicity, tumour regression, surgical and oncological outcomes.

Results: A total of 81 patients were included in the analysis. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had grade 4 toxicity. Sphincter-sparing surgery was performed for 78 (96.3%) patients. There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. Sixteen (20%) patients had a pCR. The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Three-year overall survival was 97% and the three-year disease-free survival was 85%.

Conclusions: Short-course radiotherapy with chemotherapy, radiosensitizers and delayed surgery is a feasible treatment for rectal cancer and may lead to tumour regression rate comparable with long-course chemoradiation.

Keywords:

• Rectal cancer
• chemoradiotherapy
• tumour regression
• chemoradiosensitizer
• short-course radiotherapy with delayed surgery

Introduction

Conventional short-course preoperative radiotherapy (SCPRT) is extensively used in Europe [1] and is more convenient for the patients and more economically effective when compared to long-course chemoradiotherapy (CRT). However, it is not generally accepted in the United States and several other countries due to concerns of late morbidity and lack of downstaging [2,3]. The survival benefit of preoperative radiotherapy for resectable rectal cancer is highly debateable in the total mesorectal excision (TME) era, whereas tumour dowstaging and local control, which are more easily achieved with CRT, are the main goals of neoadjuvant treatment [4].

However, the feasibility of combination of SCPRT and chemotherapy has been demonstrated in several studies [5,6]. It is possible that the combination of SCPRT and chemotherapy with delayed interval before surgery may have the benefits of both patient convenience and lower costs, typical for conventional SCPRT, and improved tumour regression and local control, associated with CRT courses. Additionally, delayed interval before surgery may solve the problem with increased perioperative complications risk, associated with SCPRT [7,8]. There are still concerns of increased morbidity of this regimen and it has not been established as an alternative to standard CRT due to lack of research data.

Local hyperthermia and high-dose metronidazole for local application have been used for radiosensitization at our institution since 2002. Their combination with different radiotherapy regimens was demonstrated to be feasible and could improve tumour regression without additional toxicity, while hyperthermia may improve the bioavailability of both chemotherapeutical agents and metronidazole. Local application of metronidazole allowed to achieve high local concentrations with lower systemic effect, thus avoiding the high neurotoxicity, typical for nitroimidazoles in radiosensitizing concentrations [9,10]. Local hyperthermia may increase treatment response both in primary tumour and involved lymph nodes in patients undergoing CRT for rectal cancer [11]. It may help compensate for a lower radiation dose of SCPRT when compared to standard CRT.

Our aims were to demonstrate the feasibility of combination of conventional SCPRT with 25 Gy delivered in five fractions, local hyperthermia and chemotherapy with capecitabine and to see whether this regimen might lead to pathological complete response (pCR) rate comparable with standard CRT.

Methods

Study design and patient selection

This study was a prospective non-randomised phase II clinical trial. To calculate the proposed sample size, we used a baseline pCR rate of 1% seen with SCPRT as our null hypothesis. To detect a 14% improvement in the pCR rate (15 vs. 1%) with the proposed treatment scheme, with a level of significance of 5 and 90% power, an accrual of 79 patients was calculated (including 5% potential data loss). A rectal tumour was defined as a lesion with its distal border within 15 cm of the anal verge. Main inclusion criteria were: histologically verified primary resectable rectal cancer cT3N0M0, cT2–3N1–2M0 or cT2N0M0 low rectal cancer. Other inclusion criteria included Karnofsky >70, absence of synchronous or metachronous malignant lesions, a haemoglobin >90 g/L, white cell count >3 × 10⁹/L, platelet count >100 × 10⁹/L, serum creatinine <150 μmol/L and serum bilirubin <30 μmol/L. Patients who received previous chemotherapy or radiotherapy were excluded from this analysis. Other exclusion criteria were: pregnancy or breast-feeding patients, comorbidity including angina, acute myocardial infarction within the previous five years, arrhythmia, history of neurological or psychiatric disorder, chronic bowel inflammatory disease and other uncontrolled severe diseases precluding administration of chemotherapy and radiation. Informed consent was obtained from all individual participants included in the study. This study was approved by the internal ethical committee and Institutional Review Board.

Pre-treatment investigations included digital rectal examination, colonoscopy, abdominal ultra-sound, contrast-enhanced abdominal and pelvic CT, double-contrast barium enema and chest X-ray. Endorectal ultrasonography and chest CT were also performed in selected patients. Pelvic CT and/or endorectal ultrasonography were used for local staging until 2011. Since 2011 high-resolution baseline magnetic resonance imaging (MRI) was routinely performed for local tumour staging. Post treatment MRI was performed occasionally and post therapy surgical treatment decision were not based on post treatment MRI findings.

Treatment

All patients received 25 Gy radiotherapy in 5 Gy fractions during five consecutive days. All patients received external-beam radiotherapy. Until 2011 patients received three-dimensional conformal radiotherapy with photon energy 6 MV. The target volume included gross tumour volume (GTV) and mesorectal, presacral, internal iliac and obturator lymph nodes. In 2011 intensity-modulated radiotherapy (IMRT) was implemented into practice. During 2011–2013 all patients received IMRT with the same radiotherapy doses. Target and avoidance structures were contoured according to the International Commission on Radiological Units 50 guidelines. The GTV was contoured on each axial CT slice based on the pre-treatment pelvic MRI. A 1.5–2.5 cm circumferential, automated expansion was added to the primary and nodal GTVs, respectively, to create a preliminary clinical target volume (CTV), which was later edited by the physician to avoid overlap into nontarget tissues. Treatment plans were constructed to deliver 7–12 modulated fields with 6–18 MV photons.

All patients received capecitabine 1000 mg/m² bid per os on days 1–14 starting on the first day of the radiation. Three 60 min sessions of 41–45 °C local hyperthermia using the capacitative “Yachta-4” device with an intrarectal applicator at a frequency of 433 MHz were performed on days 3–5 (Figure 1). Local hyperthermia was performed within 1 h of the radiotherapy session. Invasive real-time temperature control was performed for all patients. The temperature was measured on the surface of the tumour by a single flexible probe. The target surface temperatures were 45–47 °C. The deep tissue temperature was calculated using a software temperature distribution model, developed specifically for ‘Yachta-4’ device. The temperature distribution model for tumour tissue during the standard hyperthermia session is illustrated on Figure 2. The target temperatures of 42–43 °C were maintained on 0.4–1.1 cm tissue depth. The temperature level above 41 °C could not be achieved deeper than 1.5 cm. The temperature spread for fatty tissue was 3–4 cm deeper compared to tumour tissue. The target heated volume was calculated so, that at least 4 cm of mesorectal fat around the tumour was heated to 41–45 °C, thus covering most of the mesorectum. The pelvic and inferior mesorectal lymph nodes were not heated due to device limitations. All patients were intended to receive local hyperthermia; however, there were individual variations due to technical issues. Metronidazole 10 g/m² in a polymeric composition was administered per rectum on days 3 and 5 3–5 h prior to hyperthermia and radiotherapy. It contained metronidazole (20%), sodium alginate (5%), dimethyl sulfoxide (2%) and distilled water (73%).

Figure 1. Yachta-4” hyperthermia intraluminal applicator.

Figure 2. Temperature distribution model.

The interval between the completion of radiotherapy and surgery was not less than four weeks (4–10 weeks); however, it varied individually due to patient conditions and medical circumstances. On opening the abdomen, an assessment of the abdominal contents was performed and the surgical procedure was decided on, including anterior resection, low anterior resection, ultra-low anterior resection with coloanal anastomosis, Hartmann’s procedure and abdominoperineal resection. Preventive ostomy was not routinely performed.

Outcome measurements and analysis

Outcome measurements included CRT toxicity (National Cancer Institute Common Toxicity Criteria version 3 (NCI-CTC v. 3.0)), intraoperative and postoperative morbidity, sphincter-preserving rate, histopathology tumour regression (Dworak), local recurrence and distant metastases rate, overall and disease-free survival. All cases of pCR were independently reviewed by a second pathologist. The pCR rates were compared using the Chi-square test. Disease-free survival was defined as the time between study enrolment and progression of disease or death whilst on protocol. Patients who were lost to follow-up six or more months after treatment cessation were censored at the last investigation date. Overall survival was defined as the time between study enrolment and death. Disease-free survival and overall survival were estimated by the Kaplan–Meier method. All analysis was performed with Statistica software version 7.1 (StatSoft Inc., Tulsa, OK).

Results

Overall, 81 patients were recruited during 2009–2013. One patient with a clinical complete response refused surgery and was referred for watch and wait approach. Basic patient and disease characteristics are shown in Table 1. All patients received local applications of metronidazole, but 30 (37%) patients did not receive local hyperthermia because of technical issues. The most common of those were associated with the limitations of the intrarectal applicator: high tumour location (>12 cm from anal verge) in 11/30 patients and stenotic rectal tumours in 15/30 patients. The target temperature was achieved in 39 out of 51 patients, who received hyperthermia. In 12 (23.5%) patients the temperature had to be lowered 1–2 °C below the standard values due to acute painful heat sensation.

Table 1. Patient characteristics.

Characteristic	n	%
No. of patients enrolled	81	100
Sex
Male	34	42
Female	47	58
Median age, years	57
Range	24–79
Histology
Well differentiated adenocarcinoma	5	6.2
Moderately differentiated adenocarcinoma	60	74.1
Mucinous adenocarcinoma	16	19.8
Distance from external anal verge
0–5 cm	19	23.5
5–10 cm	37	45.7
10–15 cm	25	30.9
cTNM stage
cT2N0M0	7	8.6
cT3N0M0	30	37
cT2N + M0	1	1.2
cT3N + M0	43	53.1
Median time to surgery, weeks	6
4–7 weeks	65	81.3
8–10 weeks	15	18.7
Type of surgery
No operation (watch and wait)	1	1.2
Anterior resection	35	43.2
Low anterior resection with coloanal anastomosis	41	50.6
Intersphincteric resection	1	1.2
Abdominoperineal resection	2	2.5
Hartmann procedure	1	1.2

The second metronidazole application was cancelled in eight (9.9%) patients due to grade 3–4 vomiting (n = 5) or a grade 3 diarrhoea (n = 3). Sphincter-sparing surgery was performed for 78 (96.3%) patients.

Treatment toxicity

All patients completed neoadjuvant treatment according to the protocol. All toxic events are listed in Table 2.

Table 2. Treatment toxicity (NCI-CTC v. 3.0).

Adverse event	G0 (n)	G1(n)	G2(n)	G3(n)	G4(n)
Nausea	54	10	11	6	–
Vomiting	60	4	12	4	1
Diarrhoea	49	5	20	7	–
Leukopenia	78	2	1	–	–
ALT elevation	80	–	–	1	–
AST elevation	80	–	–	1	–
Proctitis	73	3	2	3	–
Cystitis	78	1	2	–	–

Grade 1–2 toxicity was observed in 28 (34.6%) patients. Ten (12.3%) patients had grade 3 toxicity and one (1.2%) patient had a grade 4 vomiting. The most common grade 3 toxicities were diarrhoea in seven (8.6%) patients, nausea in six (7.4%) patients, vomiting in four (4.9%) patients and proctitis in three (3.7%) patients.

There were no differences in grade 3–4 toxicity between the patients who received or did not receive local hyperthermia (13.7 vs. 13.3%, p = 0.96).

Surgical complications

There was an inadvertent perforation of the bowel during resection in three (3.8%) cases. In one case there was a significant bleeding from the damaged iliac vein, which was successfully managed. No other intraoperative complications were observed. A simultaneous hysterectomy for benign conditions was performed in three (3.8%) cases. Resection of the vagina was performed in one patient for suspected tumour invasion (not confirmed on histological examination). Pelvic lymph node dissection was performed in two (2.5%) cases because of intraoperatively diagnosed enlarged lymph nodes (no metastases found on histological examination in both cases).

There was no postoperative mortality. Postoperative complications occurred in 11 (13.8%) patients. The most significant of these included coloanal anastomotic leak in four (5%) patients, which required reoperation and colostomy formation, adhesive intestinal obstruction in two (2.5%) patients and eventration in one (1.3%) patient.

Infectious complications occurred in three (3.8%) patients including wound infection (n = 2) and pelvic infection (n = 1). Two (2.5%) patients had bladder retention, successfully treated after 10 courses of electrical myostimulation.

There were no differences in postoperative morbidity between the patients who received or did not receive local hyperthermia (15.7 vs. 10%, p = 0.738).

Pathology

R0 resection was achieved in 79/80 operated patients. Overall 38 (47.5%) patients had a complete or near-complete pathological response and 16 (20%) had a pCR, meaning no tumour in final specimen. Twenty-one (26.3%) patient had lymph node metastases of whom six (7.5%) had metastases in three or more lymph nodes (Table 3).

Table 3. Pathology.

Characteristic	n	%
R0	79	98.8
R1	1	1.2
ypTNM
T0N0M0	16	20
T1N0M0	3	3.8
T2N0M0	13	16.3
T3N0M0	27	33.8
T2N1M0	4	5
T3N1M0	11	13.8
T3N2M0	6	7.5
Tumour regression (Dworak)
IV	16	20
III	22	27.5
II	33	41.3
I	9	11.3

The pCR rate in patients with 4–7 weeks interval to surgery was 12 (18.2%) vs. 4 (26.7%) in patients with 8–10 weeks interval (p = 0.456).

There were no significant differences in the pCR rate between the patients who received or did not receive local hyperthermia (19.6 vs. 23.3%, p = 0.78). There was a tendency towards higher pCR rates in patients, who received local hyperthermia without lowering the temperature (9/39 (23.1%) vs. 1/12 (16.6%), p = 0.21).

Long-term treatment results

The median follow-up was 40.9 months. There were no local recurrences. Nine (11.1%) patients developed distant metastases. Six out of nine patients who experienced disease progression had a pathologic lymph node-positive rectal cancer. Three-year overall survival was 97% and the three-year disease-free survival was 88.5% (Figures 1 and 2).

Discussion

This is the first study conducted outside of Eastern Asia to demonstrate the feasibility of combination of SCPRT, chemotherapy and delayed surgery. One of the main concerns for using this approach discussed in the literature is toxicity [2,3]. Beppu et al. proposed hyperfractionated short-course radiotherapy, which is associated with lower bioequivalent dose, to reduce potential side effects [6]. However, lower bioequivalent dose may also be associated with lower tumour regression. The only study, to our knowledge, that reported attempting to integrate 5-fluoruracil-based chemotherapy into 5x5 Gy radiotherapy demonstrated high toxicity and poor tumour regression with this approach [12].

In our study grade 3–4 toxicity was comparable with the 14.6–18.2% reported for long-course CRT, but higher than 3.2–5.4% reported for SCPRT [13–15]. Grade 3 proctitis was seen in three (3.7%) patients, one of which developed an anastomotic leakage later on the follow-up. Using metronidazole as a radiosensitizer might have contributed to the toxicity, especially nausea and vomiting, typical for nitroimidazoles [16].

Many authors consider time interval before surgery to be the main factor, associated with tumour regression and local control [17,18]. Sloothaak et al. demonstrated that the waiting period of 15–16 weeks may be optimal for maximum tumour response after CRT [19]. In our study the target interval between the completion of radiotherapy and surgery was 4–6 weeks, though in 18.5% patients it was 8–10 weeks. Waiting for more than eight weeks in all patients may improve the pCR approximately by 6%, according to Petrelli et al. [20]. We did not observe significant differences between the pCR rates in patients, who had a 4–7 weeks or a 8–10 weeks interval to surgery. However, there was a clear tendency to better tumour regression in the second group and this difference could become statistically significant in a larger patient group. In our study the pCR rate was 20% compared with 7.1% reported by Beppu et al. for SCPRT with chemotherapy and ≥31 days delayed surgery [21], 8–11.8% reported by Pettersson et al. for SCPRT and >4 weeks delayed surgery [15,22] and 10% reported by Faria et al. for SCPRT and eight weeks delayed surgery [23]. It is also equal or higher than 16.1–20% reported for standard CRT [13,24], including oxaliplatin-containing CRT [25,26]. A near 12% difference in pCR compared with other SCPRT and delayed surgery studies cannot be explained only by increased time interval to surgery, but must also be associated with higher fluorpyrimidines dose and, potentially, the use of radiosensitizers.

The impact of radiosensitizers on tumour regression remains unclear and needs to be tested in a randomised setting. Local hyperthermia is a promising novel agent for rectal cancer treatment [27], and the limited data available on its clinical application shows improved tumour regression [11,28]. In our study we did not observe higher pCR rate in a subgroup of patients who received local hyperthermia. However, our study was not designed to investigate the individual role of local hyperthermia in this treatment scheme and a low number of patients do not allow to draw firm conclusions. The use of intrarectal hyperthermia applicator may not be optimal for rectal cancer patients. Nearly one third (26/81, 32.1%) of patients in our trial could not receive local hyperthermia only because of technical limitations of the intrarectal applicator. Based on this experience, we excluded patients with stenotic and upper rectal tumours from the future intraluminal hyperthermia trials.

The reported local failure rates in modern trials after the introduction of the TME technique are as low as 4.4–5% [29,30]. However, a complete absence of local recurrences during a 40-months follow up period must be associated not only with standardised surgery, but also with effective combined treatment.

The main limitation of this study is the lack of randomisation. It is unclear whether the high pCR rate observed in our study is mainly attributed to the use of capecitabine, radiosensitizers or a combination of both. The design of this trial could be modified to use the baseline pCR from SCPRT and delayed surgery studies, but there were no data on this subject at the time this study was initiated.

In conclusion, this is the first trial to demonstrate that equal tumour regression is achievable with long- and short-course CRT. These results need to be confirmed in a randomised setting and the value of individual radiosensitizers needs to be investigated. The use of intraluminal hyperthermia applicator limits the amount of patients, who can receive this treatment modality and does not allow the heating of pelvic lymph nodes, included in the radiation fields. Also it cannot be used for locally advanced tumours with rectal wall invasion more than 1–1.5 cm. The proposed treatment scheme is safe and feasible and is associated with good local control of the disease. High tumour regression rates may be associated with the use of radiosensitizers.

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

This work was supported by N.N. Blokhin Russian Cancer Research Center.