Raltitrexed concomitant with radiotherapy as neoadjuvant treatment in patients with locally advanced rectal carcinoma: a phase II study

Introduction

Methods

Table 1: Inclusion and exclusion criteria of the study

Study Design
Demographic data of the patients were obtained and a full clinical examination was performed 21 days prior to the study. Hematological evaluation, which consisted of hemoglobin, white blood cell counts, neutrophil counts, and platelet counts was performed 14 days prior to the study and on days 8, 15, 22 29, 36, and 43. The biochemical measurements including serum total protein, albumin, total bilirubin, alkaline phosphatase, aspartase aminotransferase (AST), alanine aminotransferase (ALT), sodium, potassium, and creatinine levels were carried out 14 days prior to treatment and on days 22 and 43.

According to the treatment protocol, 50.4 Gy radiotherapy was delivered in 1.8 Gy daily fractions five times per week for 5-6 weeks. A single dose of raltitrexed was infused over 15 minutes (min) 1 hour (h) prior to radiotherapy on days 1 and 22. The recommended dose of raltitrexed was 2.6 mg/m². The second dose of the raltitrexed was planned to be reduced in the case of toxicity.

Treatment response and toxicity were clinically assessed by hematological and biochemical tests in accordance with World Health Organization (WHO) suggestions for acute and subacute toxicity, WHO performance status scoring and adverse events (including gastrointestinal and urinary toxicity). Adverse events were recorded and assessed for their association with treatment by the investigator on days 22 and 33. New adverse events were also recorded for 28 days following the last dose of either raltitrexed or radiotherapy. CTC grade ¾ patients were also followed up for developed adverse events if the physician considered there was a chance to achieve grade ½ status. Immediate CBC analysis was also made for the patients with severe diarrhea of ≥ Grade II. Creatinine clearance was determined in patients with abnormal serum creatinine levels by Cockcroft formula. The size of the marker lesion and clinical resectability status after the chemotherapy along with post-resectomy pathological staging were used to assess the rectal carcinoma.

Radiotherapy treatment was planned to be delayed up to two weeks if the toxicity signs (mucositis and abdominal pain together with grade II diarrhea) or renal failure (<25 mL/min creatinine clearance) appeared. The dosage of the raltitrexed was planned to be reduced in case of hematological (leukocyte, neutrophil and platelet counts) and non-hematological (diarrhea and a creatinine clearance of 25-65 mL/min) toxicity signs.

Intensive supportive therapy was applied for severe toxicity. Patients with grade III and IV diarrhea were hospitalized to compensate fluid and electrolyte loss and were treated with antibiotics particularly if leukopenia was detected. Total parenteral nutrition was administered in case of accelerated decline in serum albumin levels. Granulocyte colony-stimulating factor (G-CSF) was given in case of sustained leukopenia.

Statistical Analysis
The total number of patients was calculated to be 28 in order to enable ≥50% resectability rate with 90% power when type 1 error and type II error were considered as 0.05 and 0.10, respectively. If there were eight responses, then the study was continued to accrue 11 patients to determine the response rate with a higher statistical accuracy. If no response was observed in patients, the response rate was less than 20%; thus, the study would stop.

The database was transferred to SPSS after all errors due to double entries were corrected. Statistical analysis was made using SPSS (version 9.0) with paired samples t test for the mean values. Chisquare and Fisher’s tests were used for the analysis of the categorical data. Kaplan-Meier analysis was used to determine time till progression and survival rates. Data were expressed as means ± standard deviation (SD) and percent (%) where appropriate. Statistical significance was set at p<0.05.

Results

Evaluation of the Tumor
As shown in Table 2, the most frequent tumor grades among the study population were T3NxM0 (n=18; 36.7%) and T3NxM (n=9; 18.4%). The ratio of patients with T3NxMx grade was 8.2% and of those with T3N1M0 was 6.1%. The tumor region in the patients were rectum (n=32; 65.3%) and pelvis (n=1; 2%). In 16 patients, the tumor region was immeasurable. Tumor size was found to be 2.38 ± 2.46 cm and 3.26 ± 3.30 cm on two subsequent measurements in 29 patients.

Table 2: Demographics and clinical features of the study population

Performance Status of the Patients
According to the performance scores, 57.1% of the patients were completely active in both initial screening and the 1st cycle. Another 53.1% were completely active in the 2nd cycle of the treatment. There was no statistically significant difference between patients of screening and treatment cycles regarding the performance status (p=1.183) (Table 3).

Table 3: WHO performance status scores of the study population

Hematological and Biochemical Parameters
Table 4 summarizes the hematological values in the 1st cycle (Day-8 and Day-15), 2nd cycle and at the completion of the study in comparison to baseline values. Hemoglobin, leukocyte and platelet counts were found to be significantly decreased at the end of the treatment period when compared to baseline levels.

Table 4: Hematological parameters of the study population

Considering the biochemical profile, serum total protein (6.95 ± 0.72 g/L vs 6.73 ± 0.6 g/L; p<0.01), albumin (3.83 ± 0.57 g/L vs 3.60 ± 0.72 g/L; p<0.001) and alkaline phosphatase (137.45 ± 88.6 IU/L vs 106.56 ± 74.86 IU/L; p<0.05) levels were decreased while AST (19.38 ± 8.53 IU/L vs 39.18 ± 26.29 IU/L; p<0.001) and ALT (17.02 ± 10.9 IU/L vs 50.06 ± 58.8 IU/L; p<0.01) levels were found to be increased in the 2nd cycle of the treatment (Day-22) compared to baseline values (Table 5).

Table 5: Serum biochemical profile of the study population

Response to Treatment
At the 1st follow-up visit, computerized tomography (CT) results revealed the complete and partial clinical response rates as 14.3% (n=7) and 28.6% (n=14), respectively. In 16.3% (n=8) of the patients, no clinically significant improvement was observed. Disease progression was 6.1% (n=3). At the 1st visit, it was observed that 33 patients (67.3%) had operable disease. Thus, in these patients, tumor resection was performed. In the tumor- resected patients, the most frequent tumor grades were as follows: T3N2M0 (n=8; 16.3%), T3N0M0 (n=5; 10.2%), T2N0M0 (n=3, 6.1%), T2N1M0 (n=3; 6.1%), and T2N2M0 (n=2; 4.1%).

At the 2nd follow-up visit, the complete and partial clinical response rates were 6.1% (n=3) and 2.0% (n=1), respectively. In 2.0% (n=1) of the patients, the treatment regimen did not seem to promote a clinical improvement. Disease progression was observed in 6.1% (n=3) of the patients.

At the 3rd follow-up visit, the complete response rate was 2.0% (n=1) and disease progression was 4.1% (n=2).

At the 4th follow-up visit, five patients had disease progression. The treatment regimen did not seem to alter the clinical course in one patient (2.0%). Disease progression was detected in three patients (6.1%).

Adverse Events
From the total of 49 patients, 37 experienced adverse events such as diarrhea, nausea, abdominal pain, polyuria, leukopenia, anemia, and tachycardia, which prolonged the duration of hospitalization. None of these adverse effects caused permanent disability or were life-threatening. The total number of adverse events was 97. The most frequently observed event was grade III diarrhea (17.5%). Grade II nausea was reported as the second most commonly experienced adverse event (15.5%). Of the 97 events, 43 were mild (44.3%), 43 were moderate (44.3%) and the remaining 10 were severe (10.3%). Raltitrexed was found to be related with 51 (52.6%) of the total adverse events, whereas radiotherapy was associated with 67 (69.1%) of the total events.

A severe adverse event (SAE) was observed in 14.3% (n=7) of the patients, and included death in three patients (due to metastases), life-threatening event in one patient and hospitalization or prolongation of hospitalization period in three patients. In those with SAEs (n=7), the disease recovered in two patients and was sustained in one patient.

In a total of 49 patients, 57.1% (n=28) completed the study. The major reasons for the drop-outs were failure of treatment (n=1), withdrawal of the consent (n=1), not coming to visits (n=9), presence of advanced disease (n=5), and death (n=4).

Survival Rate and Time to Progression
According to Kaplan-Meier survival analysis, the median survival rate of the study population was 23.69 months. In the total of 49 patients, four of them died (survival rates: 0.98 ± 0.02; 0.95 ± 0.03; 0.92 ± 0.04; and 0.46 ± 0.33). At the end of the 10th month, the study population consisted of 10 patients and at the end of 20th month there were three patients. The last patient died in the 22nd month. Cox regression analysis demonstrated no significant relationship between tumor resectability and the mortality rate of the patients (p>0.05) (Fig. 1).

Fig 1: Kaplan-Meier curve demonstrating the cumulative survival rate of the study population (n=49).

Discussion

References