Concomitant boost radiotherapy and multidrug chemotherapy in the neoadjuvant treatment of locally advanced rectal cancer: Results of a phase II study

Abstract

Background. An intensified multidrug chemotherapy regimen (raltitrexed plus oxaliplatin, Tom-Ox) plus concomitant boost radiotherapy, in the neoadjuvant treatment of locally advanced rectal cancer patients, was shown feasible in our previous study. The aim of this study was to evaluate the efficacy in terms of pathologic complete response to pre-operative therapy. Material and methods: A Phase II study was designed and clinical stage T3-T4 and/ or N ≥ 1 patients were treated with concomitant boost radiotherapy (55 Gy/5 weeks) plus concurrent chemotherapy (Tom-Ox). The primary endpoint was the assessment of efficacy in terms of clinical and pathologic response to pre-operative therapy. According to the Gehan's design study, 25 patients were enrolled. Toxicity was assessed according to the RTOG-EORTC and CTCAE v.3.0 criteria. Results: Twenty-five consecutive patients were treated. Twenty-two of the 25 (88%) patients had a partial clinical response at the time of pre-operative magnetic resonance imaging (MRI). Only one patient showed progressive systemic disease at pre-surgical revaluation and was subjected only to biopsy to evaluate pathological response. Twenty-four patients (96%) underwent surgery. Overall, pathologic complete response was observed in eight patients (32%; CI 0.95:12–55%) and only microscopic tumor foci (pTmic) in two patients (pT0-mic: 40%; CI 0.95:18–63%). Nineteen patients (76%) showed tumor down-staging. Proctitis and/or diarrhea were the most frequent acute side effects experienced. Eighteen patients had grade 1–2 toxicity (77%); whereas two patients experienced grade 3 toxicity (8%). Two-year Local control and actuarial Disease Free Survival were 100% and 91%, respectively. Conclusion. An intensified regimen of concomitant boost radiotherapy plus concurrent raltitrexed and oxaliplatin, can be safely administered in patients with locally advanced rectal cancer. This regimen produces high rates of pathological complete response. Based on available data, this type of treatment could be offered to patients with more advanced tumors (T4 or local recurrence).

Historically, local control was the main problem in locally advanced rectal cancer. Since the Total Mesorectal Excision (TME) introduction, the percentage of local recurrence has been dramatically reduced from 40% to 5–17% [1].

Radiotherapy (RT), in combination with surgery, shows an advantage in terms of improved local control and survival. The Swedish Rectal Cancer Trial reported a survival advantage for pre-operative RT [2]. The Dutch Colorectal Cancer Group showed that RT also before TME surgery is able to reduce the local recurrence incidence compared with surgery alone [3]. An update of this Trial still showed a reduced five-year local recurrence risk for patients undergoing macroscopically complete local resection [4]. The results from these and others clinical trials showed also the advantages of radiotherapy in the neoadjuvant approach [2,3,5]. Particularly, the randomized German Trial showed a decrease in local recurrence and in acute and late toxicity for pre-operative RT compared to post-operative treatment [6]. For these reasons pre-operative RT is currently widely used in cT3-4 and/ or cN1-2 M0 rectal cancer [7].

Pre-operative treatment intensification could be obtained by using altered fractionation. Indeed, non-conventional fractionation schemes have been found to be particularly effective [8]. In this framework, concomitant boost RT could be potentially advantageous due to the short potential doubling time (Tpot) of colorectal adenocarcinoma and due to the possibility to increase both dose and fractionation only to the gross tumor target volume.

In addition, the use of concomitant chemotherapy can also potentiate the efficacy of RT. EORTC 22921 and FFCD 9203 studies showed that the addition of 5-fluorouracil (5-FU) in radiation treatment further increases local control and pathological complete response (pCR) rate [9,10]. In recent years, several new agents with activity against colorectal cancer have been introduced and have improved local control and pCR rate [11–14]. Multidrug treatment has shown an increased pathological response and might be able to reduce distant metastasis rate [11–14]. Based on these data, we recently conducted a study on the feasibility of concomitant boost RT plus multidrug chemotherapy (raltitrexed plus oxaliplatin, Tom-Ox) in the neoadjuvant treatment of locally advanced rectal cancer [15]. Because the toxicity related to this intensified treatment regimen has proven moderate and acceptable, the purpose of this study is to evaluate the efficacy, in terms of clinical and pathologic response.

Material and methods

Eligibility criteria

Histologically proven locally recurrent or locally advanced (T3-4N0-2 or T2-T4N1-2, [16]) extra peritoneal rectal adenocarcinoma (above 15 cm from the anal margin) patients were included. Age > 18 years, Eastern Cooperative Oncology Group (ECOG) performance status < 2, non-pregnant and non-lactating, no prior chemotherapy, immunotherapy or RT to the pelvis were required. Unresectable metastatic disease or unfit for surgery patients were excluded.

Pretreatment evaluation included a complete history and physical examination, digital rectal examination, complete blood count, liver and renal function, colonoscopy, biopsy, computed tomography (CT) of the chest and abdomen, pelvic magnetic resonance imaging (MRI) and electrocardiogram.

Study design and end-points

This is a small phase II study of 25 patients to evaluate the treatment efficacy. The primary end point was to assess the pCR rate of concomitant boost RT (55 Gy/5 weeks, total dose) and concurrently Tom-Ox chemotherapy in the neoadjuvant treatment of locally advanced rectal cancer. Secondary endpoints were the evaluation of clinical response, toxicity and disease free survival.

The study was drawn according to Gehan's schema. It is a two-stage design for estimating the pCR rate. If no pathological complete responses are observed in the first stage of 14 patients, then the trial is terminated because this event has probability less than 0.05 if the true response probability is greater than or equal to 0.20. If at least one pCR is observed in the first 14 patients, then a second stage of accrual is carried out in order to obtain an estimate of the response probability having a specified standard error. The number of patients accrued in the second stage depends on the number of pCR observed in the first stage and the desired standard error. Gehan's design is often used with a second stage of 11 patients. This provides for estimation with approximately a 10% standard error, although this may provide very broad confidence limits [17].

Treatment

All patients were treated with concomitant boost RT (55 Gy/5 weeks) and concurrent Tom-Ox chemotherapy.

Radiotherapy

During the simulation process, patients were immobilized in prone position on an up-down table (UDT), a device aimed at reducing small-bowel irradiation. To limit the organ motion, patients were instructed to: 1) empty the bladder and drink 300 cm³ of water one hour before CT-simulation and before every daily treatment fraction; 2) to undergo enema two hours before CT-simulation and to perform treatment with an empty rectum. Simulation CT images were taken in 5 mm increments over the region of interest, after oral administration of contrast medium to allow bowel localization. The clinical target volume 1 (CTV1) included the gross tumor volume (GTV, both primary tumor and enlarged pelvic nodes) and the corresponding mesorectum plus 2 cm cranio-caudally. The CTV2 included the CTV1 plus the entire mesorectum, the entire pre-sacral space, the internal iliac nodes and the high-risk anatomical and nodal sub-sites, based on the distance of the tumor from the anal margin [18]. The planning target volume (PTV) was the CTV plus 0.8 cm margin in all directions. Organs at risk (OARs) were contoured as follows: 1) the small intestine was defined as all intestinal loops below the sacral promontory (recto sigmoid junction excluded); 2) femoral heads were contoured from the cranial extremity to the level of the lower margin of ischial tuberosities; 3) the bladder was contoured entirely with no distinction between the wall and its content. Conformal three-dimensional RT was planned (3D-RT) using the PLATO treatment planning system (TPS/Plato Nucletron B.V., Veenendaal, Netherland). A four-field box technique was used. Dose was specified according to the ICRU Report 62 [19]. Dose-volume histograms (DVHs) were calculated for the PTV and OARs. Radiotherapy was delivered by 10–15 MV photon energy. The beams were delivered by an Elekta Precise Linac equipped with standard multi leaf collimators (MLC). An early generation camera-based fluoroscopic Electronic Portal Imaging Device (EPID) by Elekta Precise Linac was used for portal imaging. Patient set-up was checked every day by comparing the megavoltage portal images (MVPIs) obtained by two perpendicular square open beams at 0° (anterior-posterior) and 90° (lateral) with the corresponding digitally reconstructed radiographies of the same beams obtained by TPS. Bony anatomy was used to verify treatment. Patients were treated only if the relative variations of bony position between the two images were within 5 mm along the three spatial directions; otherwise a set-up correction was performed. Radiation dose delivered to PTV2 was 45 Gy (1.8 Gy/fraction). A concomitant boost dose of 10.0 Gy with accelerated fractionation at 2.2 Gy/fraction, five sessions weekly, was delivered to the PTV1 during the same fraction of PTV2.

Chemotherapy

The prescribed concurrent chemotherapy schedule was as follow. Raltitrexed (Tomudex®) was administered at 3 mg/m² as a 15 min intravenous infusion and oxaliplatin (Eloxatin®) at 130 mg/m², 20 min after raltitrexed, as a two hour intravenous infusion, on days 1, 17, 35. Antiemetic prophylaxis with 5-HT 3 antagonists was administered only the day of chemotherapy delivery. Adequate hematological parameters (neutrophil count > 1.5 3 109/l and platelets > 75 3 109/l) were required before each chemotherapy infusion.

Surgery and adjuvant chemotherapy

Patients underwent radical resection of rectal cancer after six to eight weeks after the chemoradiation completion. The choice of surgical procedure (abdominoperineal resection, APR, versus low anterior resection, LAR), was left to surgeon discretion. TME was recommended and performed in all cases. Adjuvant chemotherapy was recommended for patients with positive nodes at pathologic examination [20].

Outcome evaluation

Response

Restaging was performed five to six weeks after pre-operative treatment. Restaging procedures included physical examination, pelvic MRI, chest x-ray, blood counts, and serum chemistry. Tumor response was assessed according to the RECIST criteria on pelvic MRI [21].

Down-staging was considered as any stage reduction between clinical and pathologic stage. After surgery, post-chemoradiation tumor stage was determined according to the TNM classification system recommended by the American Joint Committee on Cancer [16]. The absence of residual cancer in resected specimen was defined as pathological complete response (pCR = pT0). The presence of a number of neoplastic cells inferior to 10% was defined as microscopic residual disease (pTmic). A margin was considered to be R1 when tumor cells were noted to be into the resection margin.

Toxicity

Clinical examination and laboratory tests (including renal, liver and hematological evaluations) were performed weekly during chemoradiation. RTOG toxicity criteria [22] were used to score acute radiation toxicity and CTCAE, v 3.0 [23] to score renal and hepatic toxicity. Late radiation toxicity was evaluated by RTOG-EORTC toxicity criteria [22]. In patients with grade ≥ 3 gastrointestinal (GI), genitourinary (GU) or skin toxicity, RT was discontinued until grade 2 toxicity was resumed. In case of grade ≥ 3 liver, renal or hematological toxicity, chemotherapy was delayed until grade 2 toxicity resumed. In this case, a 25% dose reduction of chemotherapy was planned.

Follow up

Follow-up was regularly performed every three months for the first year, every six months for the next two years, and annually thereafter to evaluate acute and late toxicity and to detect early recurrence. At each follow-up visit, a digital rectal examination was performed. Liver ultrasonography and carcinoembryonic antigen determination every six months, chest x-ray and pelvic CT every 12 months, and colonoscopy every 24 months were performed.

Ethical considerations

The followed procedures were in accordance with the standards of the institutional ethics committee and of the internal board committee and with the Helsinki Declaration, as revised in 2008. All patients provided written informed consent before study entry.

Results

Patient characteristics

Twenty-five patients were enrolled. Patient and tumor characteristics are detailed in Table I. The tumor was located in the lower third of the rectum in 68% of cases (n = 17).

Table I. Patient and tumor characteristics.

Patients	25	100
Gender
Male	11	44
Female	14	56
Age (years)
Median	63
Range	48–80
Tumor location
upper third	1	4
middle third	7	28
lower third	17	68
Maximal tumor diameter (mm)
Median	40
Range	30–100
Grading
1	2	8
2	12	48
3	5	20
4	3	12
unknown	3	12
Clinical stage at baseline
T2N1M0	3	12
T2N2M0	2	8
T3N0M0	1	4
T3N1M0	2	8
T3N2M0	6	24
T4N0M0	3	12
T4N1M0	2	8
T4N2M0	6	24

Clinical response

Restaging was performed five to six weeks after pre-operative treatment in all patients by pelvic MRI. Two patients showed a complete clinical response (8%) and 20 patients achieved a partial clinical response (80%). Three minor clinical responses were considered stable disease (12%). No patients showed local progression of disease. Overall, in 22 of the 25 patients (88%) a reduced local extent of disease was demonstrated. One patient showed peritoneal seeding.

Surgery

Six to eight weeks after completion of chemoradiation, 24 patients (96%) underwent radical surgery. The patient with peritoneal metastases at pre-operative MRI underwent excisional biopsy alone. LAR was performed in 15 patients (63%) and APR in nine patients (37%). Overall, 22 patients (92%) underwent radical surgery with R0 resection margins. Two patients had R1 resection margins and were treated with post-operative radiotherapy (20 Gy/4 Gy fraction, according to NCCN Guidelines ™, version 3.2010).

The overall peri-operative complications are detailed in Table II. Two patients had cardiac complications: atrial fibrillation and atrium-ventricular block, respectively. Fever due to wound infection was the most common surgical complication (17%). Urological complication (acute urine retention) occurred in one patient. No patients had anastomotic suture dehiscence. No hospital or 30-day mortality occurred.

Table II. Peri-operative complications.

Peri-operative complications	No.	%
Cardiac	2	8
Pulmonary	0	0
Urinary	1	4
Wound infection	4	17
Anastomotic dehiscence	0	0
Hospital or 30-day mortality	0	0
Overall perioperative complications	6	25

Pathologic response and downstaging

Overall, pCR was observed in eight patients (32%; CI 0.95:12–55%) and in two patients pTmic were demonstrated (pT0-mic: 40%; CI 0.95:18–63%). Four of 12 patients (33%) with T4 tumors at diagnosis, showed pCR. Tumor and nodal downstaging are detailed in Table III, respectively. Overall, 19 patients (76%) obtained tumor downstaging. The same clinical and pathological stage (cT4N2, pT4N2) was documented in one patient. One patient showed liver metastases during surgery and received rectal resection and metastasectomy. Systemic treatment was subsequently performed.

Table III. Tumor and nodal downstaging: cTN/pTN correlation.

Stage	cT2N1	CT2N2	CT3N0	CT3N1	CT3N2	cT4N0	cT4N1	CT4N2
pTO-micN0	2	0	0	1	3	0	2	2
pT2N0	0	1	1	1	1	1	0	1
pT3N0	1	1	0	0	2	2	0	0
pT3N1	0	0	0	0	0	0	0	1
pT4N2	0	0	0	0	0	0	0	1

In bold: patients with down-staged tumor and lymph nodes. One patient with cN3 stage was not subjected to radical surgery.

Acute and late toxicity

Acute toxicity is detailed in Table IV. Proctitis and/or diarrhea were the most frequent acute symptoms. Eighteen patients experienced grade 1–2 toxicity (72%). Two patients experienced grade 3 toxicity (8%). Overall, 18 patients (72%) developed temporary and reversible (grade 1–2) changes in their liver biochemistry tests. Three patients (12%) showed grade 3 liver toxicity. Only one patient had hematological grade 4 toxicity (leukopenia and neutropenia without fever). Five patients required a dose reduction or a delay in the chemotherapy administration. Four patients discontinued RT treatment for more than seven days. Reversible peripheral neuropathy, as dysesthesia and/or paraesthesia, was present in five patients (20%). No acute renal toxicity was recorded. No treatment-related deaths occurred.

Table IV. Acute toxicity.

Grade	1	2	3	4
Acute Toxicity (%)
Skin	24	28	4	0
GI	20	52	8	0
Urinary	44	8	0	0
Liver	40	32	12	0
Renal	8	0	0	0
Anemia	20	12	0	0
Leukopenia	40	12	0	4
Neutropenia	12	4	0	4
Thrombocytopenia	8	4	0	0
Grade	1–2		3–4
Total No. of patients with acute toxicity	18		6

Fourteen patients (56%) have not shown any late toxicity. Two patients had diarrhea and bowel movement greater than five times daily and one patient developed an anastomotic stenosis 19 months after neoadjuvant therapy. Increased urinary frequency was recorded in one patient. One patient had moderate peripheral neuropathy (paraesthesia). Cumulative actuarial two-year incidence of Grade ≥ 2 GI and GU late toxicity were 25% and 4%, respectively.

Tumor control and Disease Free Survival

The median follow-up time was 15 months (range 5–50 months). To date, no patients showed local tumor recurrence after surgical resection. Two patients showed metastatic disease and systemic cytotoxic treatment was performed. Two-year actuarial Disease Free Survival was 91% (Figure 1).

Figure 1. Disease Free Survival.

Discussion

The aim of this study was to evaluate the efficacy, in terms of clinical and pathologic response, of a concomitant boost RT plus concurrent multidrug chemotherapy, in the neoadjuvant treatment of locally advanced rectal cancer.

In our previous studies [12,14], based on promising results in terms of effectiveness, we evaluated the tolerability and efficacy of a thymidylate synthase inhibitor, raltitrexed, in place of 5-FU. Raltitrexed in combination with oxaliplatin showed high rates of tumor downstaging (67%) as well as pCR and pTmic (57%) in patients with resectable transmural and/or node-positive rectal cancer [12,14].

Based on a literature review, the pCR rate with standard doses and fractions of radiotherapy, in combination with concomitant 5-FU, is 10–15% [7]. Higher rates have been obtained with protocols using higher doses of RT or multidrug chemotherapy regimens. To the best of our knowledge, a combination of both strategies (concomitant boost RT and concurrent multi-drug chemotherapy) was experienced before only in the Lyon R0-04 study. In this study, 40 patients received a dose of 45 Gy in 1.8 Gy daily fractions and a boost dose of 1 Gy once a week for five weeks (total dose 50 Gy). Two cycles of oxaliplatin, 5-FU and folic acid (FOLFOX) were administered during RT. The pCR rate was 15% and in 12 patients (30%) only a few residual cells were detected (pT0-mic: 45%). However, the authors reported increased GI and hematological toxicity (grade 3 or 4 toxicity in 42% of patients) [24].

Similar results were observed in our study. Grade 1–2 diarrhea and proctitis (n = 18; 72%) and grade 3 GI toxicity in only two patients (8%) were recorded. Overall, grade 3 and 4 toxicity was observed in 28% of patients (grade 3 in six patients and grade 4 in one patient). Furthermore, a high rate of reversible hyper-transaminasemia, resulting in a reduction of chemotherapy dose, occurred in five patients (20%). This effect was probably due to the drug combination used in the study. Since the drugs used in our study are different than those used in the Lyon R0-04 study and a comparison between the treatment toxicity is difficult, both treatments result in higher rates of toxicity compared to standard chemo-radiation treatment.

Moreover, in our study, 22 (88%) achieved a clinical response and two patients (8%) showed a complete clinical response. A pCR was obtained in eight patients (32%) and in two cases (8%), the histological examination showed pTmic. These data seem relevant given that 12 patients had advanced disease (T4) at diagnosis.

However, in both studies an intensified treatment was able to produce a high pCR rate and this result seems particularly promising given the prognostic impact of pathological complete response [25]. We can assume that the use of different drug combinations and the application of advanced RT techniques (intensity modulated radiotherapy, arch therapy) might further reduce treatment toxicity and improve tolerability and outcome.

In conclusion, our study suggests that the combination of concomitant boost RT plus concurrent two drugs chemotherapy is feasible and produces high rates of pCR. Based on available data, this type of intensified treatment could be further studied and optimized in patients with more advanced tumors (T4 or local recurrence). A study to evaluate the efficacy of an orally-administered substitute of 5-FU (capecitabine) in combination with oxaliplatin and concomitant boost RT has been planned.

Acknowledgements

We sincerely thank Dr Perla Avegno for reviewing the manuscript. This paper was presented in part at the XXIX Congress of European Society for Therapeutic Radiology and Oncology, Barcelona, Spain, September 12–16, 2010. All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work.