Evaluation of Preoperative Short Course Intensity Modulated Radiation Therapy in Treatment of Locally Advanced Rectal Carcinoma.

INTRODUCTION

Neoadjuvant radiotherapy (RT) is frequently used in the treatment of locally advanced rectal carcinoma trying to achieve down-staging, sphincter preservation, as well as improvement in local control (LC) or even survival. ^1,2 There is still a debate on the optimal fractionation of RT, the timing of surgery, and the utilization of concurrent chemotherapy.³

Conventionally fractionated concurrent chemoradiotherapy (CCRT); (1.8–2 Gy ×25–28 fractions) followed by surgery after 4-8 weeks is the most commonly used approach. ^(4-7) This interval gives time for recovery from early toxicity and allows for down-staging, and achieving a pathological complete response (pCR). ^4,6,7,8,9,10

However, it increases morbidity, and, in some trials, mortality.^11,12

Short-course radiotherapy (SCRT) with immediate surgery; 25 Gy over 5 fractions and surgery within the following week has been commonly used in Sweden and some other countries in Northern and Western Europe. ^4,5,6,7

Many trials have examined the most appropriate treatment schedule during the last 2 decades, Polish and Australian trials compared long-course CCRT with SCRT with immediate surgery,^14,15 no significant differences were observed in postoperative complications, LC, late toxicity, or survival; nevertheless, a significantly lower acute radiation toxicity was observed with SCRT.

Postponing the time of surgery after SCRT also seems to be beneficial in inducing down-staging, pCR, and reducing postoperative morbidity than SCRT with immediate surgery, however. it did not increase the rate of sphincter-saving procedures and curative surgery. ^16,17,18,19

Traditionally, pre-operative RT has been delivered via three-dimensional conformal RT (3D-CRT) with three or four-field techniques for rectal cancer. More advanced techniques have been widely and successfully used for head-and-neck, prostate, and other cancers, such as intensity-modulated radiotherapy (IMRT),^20,21however, its potential clinical benefits remain debatable in rectal cancer.²²

The study aimed to evaluate the efficacy and tolerability of preoperative short-course IMRT with delayed surgery in patients with resectable locally advanced rectal carcinoma.

 PATIENT AND METHODS

The current work is a prospective study, including patients with a pathologically confirmed diagnosis of rectal carcinoma, in Clinical Oncology and Nuclear Medicine Department, El Hussein Hospital, Faculty of Medicine, Al-Azhar University during the period between June 2016 and August 2018. Approval of the ethical committee and written informed consent from every patient was obtained.

Eligibility criteria:

• Resectable locally advanced rectal adenocarcinoma; clinical stage II-III.

• Age more than 18 years and less than 80 of both genders.

• Performance Status ≤ 2 ECOG scale.

• Ejection fraction > 55%.

• Adequate laboratory investigations. 

• Medically fit for surgery.

• Patients without any primary treatment for their current disease (surgical, chemotherapy, or radiotherapy).

Ineligibility Criteria:

• Tumors extending above 15 cm from the anal verge.

• Pregnant women.

• Patients with synchronous tumors of the colon. 

• Patients with a history of malignancy except for basal cell carcinoma.

• Patients presented with intestinal obstruction.

• Obese patients (> 120 kg).

• Severe skeletal deformity or any disease interfering with patient alignment and positioning for radiation therapy delivery.

All patients were subjected to clinical examination, colonoscopy, CT chest, abdomen and pelvis, Pelvic MRI with a series of laboratory investigations to assess the extent of disease and the presence of co-morbidity if any.

Staging of the disease was assessed according to the AJCC cancer staging system the 7^th edition, ²³ and the ECOG scale was used to assess the performance status. ²⁴

Tumors were classified regarding the distance of the lower extent of the primary tumor from anal verge into:

High: > 10 cm.

Middle: > 5 cm and ≤ 10 cm.

Low: ≤ 5 cm.

Mesorectal facia (MRF) was considered involved when the distance of the tumor to the MRF of ⩽1 mm.

Trial design:

In this prospective study, patients were planned to receive preoperative short course IMRT (25 Gy / 5 fractions in 5 consecutive days), then total mesorectal excision (TME) was planned 4-8 weeks after completion of neoadjuvant treatment. Target volumes and organs at risk were defined according to Radiationtherapy Oncology Group (RTOG) Consensus Panel Contouring Atlas. ^25,26

An IMRT plan designed to cover 98 % of PTV with 95 % of the treatment dose while delivering 105% of the treatment dose to below 10%, and not delivering ≥110% of the treatment dose to the PTV. We kept the maximal irradiation dose of the bladder under 24 Gy, bowel under 25 Gy, and femur heads under 20 Gy and kept the D50% of the above 3 organs at risk (OARs), irradiated ≤20 Gy, ≤13 Gy, and ≤15 Gy respectively.

Plans were generated concerning delivery using only 6-MV photons via linear accelerator (Varian Medical System). PTV coverage had been given the highest priority, then minimization of dose to bowel while the intermediate priority for reducing the dose to the bladder, and femoral head/neck. Quality assurance (QA) was done before starting treatment for every case, verification with an electronic portal image device (EPID) was done before every fraction.

Acute and late radiotherapy adverse effects were graded according to RTOG/EORTC radiation toxicity grading.²⁷

Response evaluation:

Abdominopelvic CT, MRI pelvis and colonoscopy were done for all cases about one week before surgery.  A tumor and/or nodal down-staging is considered when ycT and/or ycN is lower than cT and/or cN as defined by MRI, while clinical CR represented the absence of tumor by clinical examination, MRI, and colonoscopy. 

Surgery:

TME (Total mesorectal excision) was planned 4-8 weeks after the completion of radiotherapy, and choice between low anterior resection and abdominoperineal resection and whether a temporary colostomy should be performed was left to the surgeon's discretion.

Surgery was considered adequate if achieving R0 resection (absence of macroscopic or microscopic residual disease), while pCR was considered when no malignant cells are observed in the surgical specimen.

Post-operative complications were the reported complication occurring within one month from surgery.

Adjuvant treatment:

Following wound healing, patients received six months of adjuvant chemotherapy either FOLFOX-4 regimen or Degramont regimen, the selection was based on the stage of the disease and the expected patient tolerance.

Follow up:

After finishing adjuvant chemotherapy regimen patients had scheduled visits with investigations (CEA every 3 months, CT scan every 6 months, and colonoscopy in 1 year, then every 2–3 years if negative).

Disease-free survival (DFS) was the time from surgery to confirmed local recurrence, distant metastases, or death whichever occurred first, patients who neither relapsed nor died were censored at last assessment before a loss to follow-up.

Overall survival was the time from diagnosis till death, with survivors being censored at the time of the last follow-up. Living patients or patients lost to follow-up were censored on the last known alive date.

Statistical Methods:

Statistical presentation and analysis of this study were conducted via SPSS V22, using the mean, standard deviation, student t-test, chi-square, linear correlation coefficient, and analysis of variance [ANOVA] tests, survival analysis was done using Kaplan-Meier method, and the p-value was considered significant if ≤ 0.05.

RESULTS

The current prospective study included 37 patients with a pathologically confirmed diagnosis of locally advanced resectable rectal adenocarcinoma fulfilling the eligibility criteria. Table (1) demonstrates the clinicopathologic features of the patients.

The whole study group received preoperative IMRT 25 Gy / 5 fractions over 5 consecutive days without any interruptions. PTV coverage, doses received by OAR, homogeneity index, and conformity index are shown in table (2)

Down-staging was observed in 20 patients (54.1%); it was noticed that 4 patients (10.8%) had a clinical CR, 16 patients (43.2%) had a partial response (PR), 15 patients (40.5%) had stable disease (SD) while 2 patients (5.4 %) had disease progression (PD). Factors affecting clinical down-staging are shown in table (3).

It was noticed that patients with cN2 disease, radiological EMVI, and radiologically involved mesorectal facia (MRF) tend to have a poor clinical response with statistically significant P-values.

Only 35 patients (94.6%) submitted to surgery while one patient (2.7 %) refused surgery as she achieved clinical CR and the other one (2.7 %) was unfit for surgery.

The median period between radiotherapy and surgery was 7.3 weeks (range of 4.3-8 weeks), Curative surgery was done in 33 patients (94.3%) only; 17 of them (51.5%) had an anterior resection and the remaining 16 patients (48.5%) had APR. On the contrary, 2 patients had laparotomy only but the tumor was found to be irresectable. For patients having low rectal tumors at presentation (25 patients), sphincter sparing was successfully achieved in 7 of them (28%).

Histopathological examination and pathological TNM staging were done; histopathology evaluation results are shown in table (4).

All the 33 patients who submitted to curative surgery received adjuvant chemotherapy; 26 patients (78.8%) received the FOLFOX-4 regimen while 7 patients (21.2%) received the Degramont regimen, which was given to patients who experienced pCR and patients who were not expected to tolerate FOLFOX-4 regimen.

Most of the patients tolerated radiotherapy well, as no patients suffered from grade III or IV hematological toxicity, and no grade IV non- hematological toxicity was reported.

 Only two patients (5.4%) had grade III early skin toxicity with no reported late skin effects, no patients suffered from GIII early bowel or bladder toxicity on the contrary GIII late bowel and bladder toxicity was reported in 5.4% and 2.7% respectively, table (5).

Surgical complications were reported in 37 % (13/35) of the operated patients, wound infection was the most frequently reported surgical complication and it occurred in 14.2% (5/35) of the patients; three of them (60%) were submitted to APR, the next most frequent complication was delayed wound healing and it was reported in 11.4% (4/35) of the patients; three of them (75%) also were submitted to APR, table (6).

Only 33 patients who submitted to R0 resection were evaluated for PFS and OS; The median follow up period was 23 months, by the end of this study, 6 patients (18.2%) died and 27 patients (81.8%) were still alive.

9% of the patients (3/33) suffered from a locoregional recurrence, 21.2% (7/33) had distant metastasis while 6% (2/33) had simultaneous systemic and locoregional recurrences.

The liver was the common partner in all cases with distant metastasis as it was reported in all the seven patients (100%) with distant metastasis, then lung, para-aortic lymph nodes and bone with 2 cases (28.6%) for each of them and the lowest was the skin which was present only in one patient (14.3%).

Table 1: The clinicopathologic characteristics of the study group.

Table 2: Radiotherapy parameters.

Table 3: Factors affecting clinical down staging:

Table 4: Histopathology evaluation results.

Table 5: Neoadjuvant RT related toxicity.

Table 6: Surgical complications.

The median DFS and OS have not been reached. The cumulative 1 year and 2 years DFS were 88 % and 71 % respectively, while the cumulative 1 year and 2 years OS were 90.1% and 80 % respectively, Figures (1&2).

 Fig. 1: Disease free survival.

 Fig. 2: Overall survival.

Factors affecting DFS and overall survival were studied, (Table 7,8). It was found that patients younger than 40 years old and patients with ypN2 stage have significantly worse PFS but there was no significant impact on OS, on the other hand, other prognostic variables Showed no statistically significant effect on either PFS or OS.

DISCUSSION

The optimal RT fractionation, concomitant chemotherapy, and the proper timing of surgery in patients suffering from locally advanced resectable rectal carcinoma has been much debated.

The general idea of the current prospective study was to explore the safety of SCRT with delayed surgery and its efficacy to induce Down-staging, pCR, sphincter preservation, and the impact of utilizing IMRT in reducing the dose to OAR.

SCRT followed by immediate surgery, doesn’t induce down-staging, ⁽²⁸⁾but a longer period between RT and surgery leads to a higher down-staging rate (44.2% vs. 13%).¹⁹ Moreover, a Swedish retrospective study reported that 74 % of the patients had tumor regression on MRI after a median of 4 weeks after the completion of RT but it was noticed that only 55.4 % of the patients had MRI reassessment.²⁹

In our study the rate of down-staging was 54.1%, It was noticed that patients with cN2 disease, radiological EMVI, and radiological involved mesorectal facia (MRF) tend to have a statistically significant worse clinical down-staging.

A Korean study showed a higher conformal radiation dose to the target and significantly reduced the dose to OAR when using short course IMRT compared to the four-box field (3D-CRT), ³⁰ our study results were consistent regarding PTV coverage and femoral head mean dose but Bowel and bladder mean doses were higher than those reported in the IMRT arm but still better than the conformal radiotherapy results, the difference may be attributed to the utilization of tomotherapy in the Korean study.  

In our study, severe early and late toxicity were reported in 5.4% and 8.1% of the patients respectively, Polish trial reported that the incidence of severe early and late adverse effects in SCRT arm was 3.2 % and 10.1% respectively.¹⁴

Stockholm III trial reportedsevere acute toxicity in <1% of the patients receiving SCRT with immediate surgery group, 4.2 % of the patients in SCRT with delayed surgery group and 5 % in the CCRT group, and it was thought that acute radiation toxicity was masked by surgical complications in the SCRT with immediate surgery group. ¹⁷

A retrospective study including patients who received SCRT then delayed surgery, Severe radiation‐induced toxicity was reported in 5.4 % of them.²⁹

Polish trial demonstrated that the rates of postoperative complications for the SCRT with immediate surgery group and the long course CCRT group were 27% vs 21%, respectively but it was noticed that only 39 % of the patients had APR.³¹

In an older Dutch trial, it was noticed that patients who had an abdominoperineal resection, after preoperative RT had more perineal complications than those assigned to surgery alone 26 % vs. 18 %.³²

Stockholm III trial showed a significantly lower incidence of postoperative complications in the SCRT followed by delayed surgery vs. SCRT with immediate surgery, (41 % vs. 53%).¹⁷

In our study, postoperative complications were reported in 37 % of the patients and it was obvious that most of them had APR.

It is suggested that patients with a pCR might have better DFS and OS.¹⁰ In our study, we reported a pCR rate of 9%, and it was consistent with the results of a retrospective study held in the Netherlands that found a significantly lower pCR rate in patients treated with SCRT with delayed surgery compared to long course CCRT (9.3% vs. 17.5% respectively). ¹⁸

Stockholm III trial reported a pCR rate of 11.8% in patients receiving SCRT with delayed surgery.¹⁶

Table 7: Disease free survival and its relation to the prognostic factors.

Table 8: Overall survival and its relation to the prognostic factors.