Raltitrexed (‘Tomudex’) and radiotherapy can be combined as postoperative treatment for rectal cancer

Annals of Oncology 11: 1023-1028, 2000. © 2000 Kluwer Academic Publishers. Primed in the Netherlands.

Original article Raltitrexed ('Tomudex') and radiotherapy can be combined as postoperative treatment for rectal cancer N. Botwood,1 R. James,23 C.Vernon1 & P. Price1 ^Department of Clinical Oncology, Hammersmith Hospital, Imperial College School of Medicine, London; 2 Christie Hospital, Manchester; ^Current address: The Kent Cancer Centre, Maidstone, UK

Results: A total of 22 patients entered the study, 17 of whom had Dukes' stage C disease. All three patients entered at a dose Background: The optimal adjuvant therapy for operable rectal level of 3.0 mg/m2 experienced dose-limiting toxicity (DLT) cancer is likely to be a combination of radiotherapy and chemo- (2 patients had grade 3 leucopenia and 1 patient had grade 2 therapy. Raltitrexed ('Tomudex') is a specific thymidylate leucopenia and grade 3 diarrhoea); however, only 2 of 11 synthase inhibitor with a convenient administration schedule, patients entered at a dose level of 2.6 mg/m2 experienced DLT acceptable and manageable toxicity, radiosensitising proper- (1 patient had grade 4 neutropenia and 1 patient died probably ties, and proven efficacy in the treatment of advanced colo- due to aspiration pneumonia unrelated to treatment). The rectal cancer. It may, therefore, offer advantages compared most common haematological toxic events were leucopenia with standard 5-FU chemotherapy regimens used in colorectal (8 patients) and anaemia (6 patients). Only four haematologcancer. The aim of this phase I, dose-escalation study was to ical or biochemical toxic events were of grade 3 or 4. Other determine the recommended dose of raltitrexed for use with common toxicities were diarrhoea and nausea, which occurred postoperative pelvic radiotherapy in patients with rectal cancer. in 15 and 9 patients, respectively. Patients and methods: Patients with resected Dukes' stage B Conclusions: This study demonstrates that raltitrexed can or C rectal cancer were treated with a combination of ralti- be combined with postoperative radiotherapy for treatment of trexed and radiotherapy (50.4 Gy at 1.8 Gy per fraction over patients with Dukes' stage B or C rectal cancer. The recomfive to six weeks). At least three patients were treated at each of mended dose of raltitrexed in this setting is 2.6 mg/m2, which three escalating raltitrexed dose levels (2.0, 2.6 and 3.0 mg/m2) is close to the full monotherapy dose. once every three weeks. Toxicity was assessed by the recording of WHO adverse events and biochemistry and haematology Key words: chemoradiation, postoperative radiotherapy, raltideterminations. trexed, rectal cancer, 'Tomudex' Summary

Introduction

Rectal cancer is one of the most prevalent cancers in the Western world, resulting in an estimated 36,000 new cases and 8,800 deaths in 1998 in the US alone [1]. For many patients, surgery is currently the mainstay of treatment for rectal cancer; however, local recurrence following surgery alone is common, with relapse rates of approximately 25% in patients with Dukes' stage B or C disease [2, 3]. Post-operative radiotherapy, which is usually started four to six weeks following surgery, can reduce the risk of local recurrence following surgery for rectal cancer [4, 5]. Cummings [5] reviewed 4 trials [2, 3, 6-8], including a total of 1144 patients, that compared surgery alone with surgery and postoperative radiotherapy in patients with Dukes' stage B or C rectal cancer. There was no consistent improvement in five-year survival; however, each of the studies found a reduced frequency of local recurrence following radiotherapy and surgery compared with surgery alone, although these differences were not

statistically significant. Nevertheless, another study, conducted by the MRCRCWP in 469 patients with Dukes' stage B or C rectal cancers, did find a statistically significant improvement in local recurrence rates following postoperative radiotherapy compared with surgery [4]. A significantly lower proportion of patients in the postoperative radiotherapy group experienced local recurrence (21% vs. 34%; P - 0.001), although no significant difference in survival emerged. Adjuvant chemotherapy is also increasingly being used to treat patients receiving surgery for Dukes' stage B or C rectal cancer, and may improve survival in such patients compared with surgery alone [2]. The NSABP (National Surgical Adjuvant Breast and Bowel Project) protocol R-01 trial found that patients who received postoperative chemotherapy had a significantly improved disease-free survival compared with those patients who received surgery alone (42 vs. 30 months, P = 0.006) and an overall survival advantage (P = 0.05). However, these significant benefits were restricted to male patients and chemotherapy was more advantageous

1024 in younger patients and those with Dukes' stage B disease. The optimal adjuvant therapy for operable rectal cancer has yet to be determined; this may be provided by a combination of radiotherapy and chemotherapy. Chemotherapy with 5-FU in combination with radiotherapy has been used in both the preoperative and the postoperative setting. Krook et al. [9] found that a combination of post-operative radiotherapy and 5-FUbased chemotherapy reduced the recurrence of rectal cancer by 34% {P - 0.0016) and the rate of cancerrelated deaths by 36% (P - 0.0071) compared with postoperative radiotherapy alone. Raltitrexed (Tomudex') is a quinazoline folate analogue which acts as a thymidylate synthase (TS) inhibitor and has a convenient administration schedule (15-min infusion once every three weeks). It has demonstrated efficacy as monotherapy in the treatment of advanced colorectal cancer in 3 large, phase III, randomised trials comparing treatment with raltitrexed against 5-FUleucovorin (LV) [10-12]. Combination therapy is aimed at improving response rates and survival [13]. Raltitrexed is an ideal candidate for use in combination therapy for treatment of colorectal cancer due to its efficacy as a single agent, its manageable toxicity profile and convenient administration schedule. Raltitrexed is currently undergoing evaluation as combination therapy with other cytotoxics including 5-FU [14] and oxaliplatin [15] in patients with advanced colorectal cancer. Such combinations of treatments with different mechanisms of action, and preferably non-overlapping toxicity profiles, may result in enhanced response rates whilst maintaining acceptable tolerability. Similarly, combined treatment modalities, such as raltitrexed and radiotherapy, may provide the optimum treatment before or after surgery for patients with operable rectal cancer. The aim of this phase I dose-escalation study was to assess the tolerability profile of the combination, and thus define the recommended dose of raltitrexed for use with postoperative pelvic radiotherapy in a subsequent phase II investigation.

had been curatively resected, a WHO performance status $ 2 , a life expectancy of at least 12 weeks, and were considered appropriate to receive systemic adjuvant chemotherapy and radiotherapy. Principal exclusion criteria were previous systemic chemotherapy for colorectal cancer: previous radiotherapy to the planned exposure area; extensive metastatic disease; abnormal blood cell counts (white blood cells < 4 0 x 1O9/1, unless neutrophil count 3=2.0 x 1O9/1, or platelet count < 100 x 109/l) or biochemistry (serum creatinine > upper limit normal [ULN], serum bilirubin 5= 1.25 x ULN or aspartate aminotransferase or alanine aminotransferase >2.5 x ULN); other serious medical conditions. Patients were withdrawn from treatment due to toxic events (see below), protocol non-compliance or withdrawal of consent.

Treatment Treatment was initiated four to six weeks following curative resection of the tumour by anterior resection or abdominoperineal resection. Patients were treated with radiotherapy (28 fractions at 1.8 Gy per fraction using 6-10 mV photons) 5 times per week for 5-6 weeks, with a standard 3-field technique to the posterior pelvis. Raltitrexed was administered as a 15-minute infusion 1 hour before radiotherapy on days 1 and 22 (3-week interval) at 3 dose levels, dose level 1 2.0 mg/m 2 , dose level 2 2.6 mg/m 2 and dose level 3 3.0 mg/m 2 , according to the dose escalation schedule detailed below. At least three patients were studied at each dose level; intra-individual dose escalation did not occur. Further patients were entered at the likely recommended dose to confirm the tolerability at this dose level. The dose of raltitrexed was delayed and/or reduced in the presence of toxicity or the development of renal impairment. If unacceptable or clinically relevant toxicity occurred, dose administration was delayed for a maximum of 14 days. If, after 14 days, toxicity had not resolved to acceptable levels, the patient received no further doses of trial chemotherapy. Diarrhoea and mucositis were to have resolved completely, with the exception of grade 1 or 2 diarrhoea if it was thought to be due to the residual effect of surgery and its combination with radiotherapy. Haematological and liver function parameters were to have returned to levels satisfying the trial selection criteria. Raltitrexed treatment was stopped if measured creatinine clearance was ^ 25 ml/min, or the dose reduced by 50% if creatinine clearance was 25-65 ml/min at the time of intended treatment as clearance of raltitrexed has been shown to be longer in patients with renal impairment [16]. If radiotherapy toxicity was considered severe (such as significant symptomatic moist skin desquamation or WHO grade 2 diarrhoea with abdominal pain) on day 21 of the cycle, a second dose of raltitrexed was not administered. In addition, the second dose of raltitrexed could be reduced, in the light of emergent haematological (leucopenia, neutropenia and thrombocytopenia) and/or non-haematological toxicities. The degree of dose reduction was dependent on the highest grade of each toxicity (Table 1).

Patients and methods Dose-escalation schedule Study design This non-comparative, dose-escalation study of raltitrexed in combination with a fixed dose of radiotherapy was conducted in patients with rectal cancer at two centres. All patients provided written informed consent to participate in the trial. A minimum of three patients were to be treated at each dose level with at least an additional six patients treated at the recommended dose. The study was conducted in accordance with the principles of Good Clinical Practice, according to the Declaration of Helsinki and subsequent amendments, and approved by the ethics committees of the participating centres.

Patients Eligible patients were at least 18 >ears of age. had microscopically confirmed Dukes" Stage B or C adenocarcinoma of the rectum which

Patients were allocated to a particular dose level of raltitrexed according to the dose-escalation schedule (Figure 1). If three of six patients experienced dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) had been reached. If four or more patients experienced DLT at the first dose level then the MTD was undefined. However, if this occurred at dose levels 2 or 3, the MTD was defined as one dose level below. The recommended dose was defined as one dose level of raltitrexed below the MTD. Dose-limiting toxicity for radiotherapy was defined as: significant and symptomatic moist skin desquamation at day 21; WHO grade 2 diarrhoea with abdominal pain: investigator concern at day 21 that general toxicity, if continued, would necessitate incompletion of radiotherapy treatment; other pelvic toxicities considered by the investigator to indicate that the therapies were associated with unacceptable clinical side effects. The use of a grade 2 haematological toxicity to define DLT was used here as these would be considered unacceptable

1025 3 pts entered at dose level

±

I DLT in 1 / 3 or 2 / 3 pts |

| Further 3 pis at same dose level

DLT in 1 / 6 or 2 / 6 pts

DLT In 3 / 6 pts MTD reached No further dose escalation

3 pts at next dose level*

| DLT in 3 / 3 pts |

Table 1. Second dose of raltitrexed to be administered based on worst WHO grade of haematological and non-haematological toxicity after the first dose (expressed as a percentage of the first dose).

7

Non-haematological toxicities

No further raltitrexed at this dose or above

DLT in 4 / 6 or 5 / 6 pts MTD is undefined (dose level I) or dose below (dose levels II or III)

Repeat steps as for dose level I

Haematological toxicities Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

100 100 100 75 50

100 100 100 75 50

75" 75" 75" 75 50

50 50 50 50 0

0 0 0 0 0

If £2/6 patients experience DLT at dose level 111, MTD will not have been reached and this dose will be considered as the RD MTD: maximum tolerated dose DLT: dose-limiting toxiclty

Figure 1. Planned dose-escalation schedule.

side effects from radiotherapy alone and suggest additive toxicity This grade could lead to interruption of radiotherapy, thus compromising treatment and so was considered 'unacceptable'. Dose-limiting toxicity for raltitrexed was defined as drug-related WHO grade 3 or 4 neutropenia or thrombocytopenia or any drug-related grade 2, 3 or 4 nonhaematological toxicity.

Tolerability assessments The medical history of the patient was recorded within 21 days prior to the first dose of raltitrexed and a full physical examination was performed at baseline. Adverse events were recorded and classified according to WHO grade and the investigators' assessment of the relationship to study treatment. All adverse events were followed to resolution and patients were monitored for 28 days after the last treatment with raltitrexed or radiotherapy for any new adverse events. Blood samples were collected for biochemical (10 ml) and haematology (5 ml) analyses. Biochemistry assessments were performed within 14 days prior to the first dose of raltitrexed. within 7 days prior to the second dose and 3 weeks after the second dose of raltitrexed. Haematology assessments were performed weekly, within 14 days prior to the first dose of raltitrexed, within 3 days prior to the second dose and, finally, 3 weeks after the second dose. If a patient experienced diarrhoea WHO grade 2 or more in severity a blood cell count was performed immediately. Similarly, if patients developed abnormal serum creatinine values their creatinine clearance was calculated. All patients with grade 3 or 4 laboratory toxicities at the end of the treatment period were followed up until they had returned to grade I or 2, unless they were thought unlikely to improve due to the underlying disease.

Results A total of 22 patients entered the study, 17 of whom had Dukes' stage C disease (Table 2). Eight patients were entered at dose level 1, eleven at dose level 2 and three at dose level 3. Patients were recruited simultaneously at the two participating centres. The most common non-haematological and nonbiochemical toxicities were diarrhoea and nausea, which were experienced by 15 and 9 patients, respectively (Table 3). Diarrhoea, nausea and vomiting were considered to be related to the combination of radiotherapy plus raltitrexed treatment, and urinary adverse events,

" If WHO grade 2 diarrhoea was considered to be due to the residual effect of the surgery combined with radiotherapy a dose reduction was not mandatory.

Table 2. Patient characteristics. Characteristic

Patients

Total Sex Male Female Age (years) Median Range Surgery Anterior resection only Anterior resection plus temporary ileostomy Abdominopenneal resection Tumour stage (Dukes' grade)" Bl B2 B3 Cl C2

22 14 8 61.5 42-76 13 4 5 2 2 1 13 4

" Dukes'grading according to modified Astler-Coller system.

such as increased frequency, hesitancy and dysuria, were considered to be related to radiotherapy alone. None of these adverse events was considered to be related to raltitrexed treatment alone. Haematological and biochemical toxicities are shown in Table 4. A total of 18 haematological and biochemical toxic events were experienced, the most common of which were leucopenia (8 patients) and anaemia (6 patients). Only 4 of these toxicities were grade 3 or 4: grade 3 elevation in transaminases at dose level 1, grade 4 leucopenia at dose level 2, grade 4 neutropenia at dose level 2, and grade 3 leucopenia at dose level 3. The principal DLTs were diarrhoea, leucopenia, neutropenia and elevation of transaminases. Of the three patients initially entered at dose level 1, two experienced a DLT (Table 5). However, none of the further five patients recruited at this dose level experienced a DLT and no DLTs were experienced by the first four patients entered at dose level 2. All three patients entered at dose level 3 experienced a DLT; therefore, dose level 3 was

1026 Table 3. Treatment-emergent adverse events (excluding haematological and biochemical toxicities) and their relationship to treatment.

Table 4. Haematological and biochemical toxicities at each dose level. Dose level

Adverse event

Diarrhoea

Grade

No. Relationship to treatment of pts Radio- Ralti- RadioUnretherapy trexed therapy/ lated raltitrexed

1 1 1 2

Grade

No. of pts

Anaemia Elevation in transaminases Anaemia Leucopenia

1 5b 2 4b 3 lb 4 lc Worsened11 4

Urinary problems Frequency 3 Hesitancy 1 Dysuria 1 Skin rashes 1 Pruritus and erythema 2 Nausea 1 Vomiting 2

Toxicity

Neutropenia Elevation in ALT Anaemia Leucopenia •

1 9 1

*' Relationship to treatment was assessed by the investigator. b In patients who underwent anterior resection only. c In patients who underwent anterior resection plus temporary ileostomy. d Equivalent to WHO grade 2. Patients who could not be assessed by standard WHO criteria due to the presence of stoma. Other unrelated adverse events during treatment included gastritis, pain in rectum, back pain, finger numbness and headache.

the MTD. A further 7 patients, of whom 2 developed a DLT, were entered at dose level 2, to define better the tolerability profile at the recommended dose. One death occurred on the study. The patient had had an excessive alcoholic intake, and developed an aspiration pneumonia and died. There was no evidence of any treatmentrelated toxicity and the death has been classified as unrelated to treatment.

Discussion Dose-limiting toxicity was observed in all three patients who were administered a raltitrexed dose of 3.0 mg/m2 in combination with radiotherapy as postoperative treatment. Therefore, the recommended dose of raltitrexed in this setting is 2.6 mg/m 2 , which is a marginal decrease in the raltitrexed dose compared with the dose of 3.0 mg/m2 recommended for monotherapy. This represents a dose reduction of raltitrexed compared with that used for standard treatment (3.0 mg/m2) to avoid pelvic toxicity and leucopenia observed with combination chemoradiation. The reduction in the dose of raltitrexed is of a similar magnitude to that required for 5-FU when used in combination with pelvic radiotherapy [17]. Determination of the recommended dose of raltitrexed for use with radiotherapy for post-operative management of rectal cancer has enabled an ongoing phase II trial to assess the effectiveness of such treatment. A

Elevation in transaminases

Table 5 Dose-limiting toxicities experienced at each dose level and the resulting treatment interruption. Dose level

No. of pts recruited

No. of pts with DLT

Toxicity reported (no. of pts)

Treatment interruption

1

3 (initial)

2

Grade 3 elevation in transaminases of > 14 days duration (1)

Missed 2nd cycle of raltitrexed

Grade 4 diarrhoea of 10 days duration from day 12 after the 2nd cycle (1)

Radiotherapy abandoned at 34 Gy

Grade 3 leucopenia (2)

Missed 2nd cycle of raltitrexed

Grade 2 leucopenia and grade 3 diarrhoea (1)

Missed 2nd cycle of raltitrexed

Grade 4 neutropenia (1) Death (thought unrelated to treatment) 3 (I)

Missed 2nd cycle of raltitrexed Missed 2nd cycle of raltitrexed

1

5 0 (further)

7 2 (further)

a Patient thought to have died of aspiration pneumonia following a bout of excessive alcohol intake.

combination of radiotherapy and raltitrexed may be expected to have favourable efficacy due to the radiosensitising properties of raltitrexed both in vivo and in vitro [18]. Raltitrexed enhanced the cytotoxic activity of radiation in HT-29 human colon carcinoma cells and SCC-25 human head and neck squamous carcinoma cells when maintained under normal or hypoxic conditions, probably by inhibiting the repair of radiation-induced DNA damage. An additive response was also seen when raltitrexed was administered along with radiation therapy to mice bearing the Lewis lung carcinoma or the HT-29

1027 colon carcinoma. Furthermore, TS expression has been shown to be an important prognostic indicator of disease-free survival and survival in patients with rectal cancer [19]. At five-years' follow-up, 60% of patients with low TS levels were alive compared with only 40% of patients with high TS levels (/> < 0.01). Moreover, patients with high TS levels significantly benefited from adjuvant 5-FU treatment compared with surgery alone. As raltitrexed is a more specific TS inhibitor than 5-FU, it may provide an advantageous treatment option as chemoradiation in patients with operable rectal cancer. There remains some debate regarding the optimal timing of chemoradiation; pre- or postoperative. It has been suggested that preoperative chemoradiation may offer benefits over postoperative treatment, such as reduced pelvic toxicity and an increased chance of performing sphincter-sparing surgery [20]; however, these modes of administration have not been compared in well-controlled clinical trials. The results of an ongoing phase I trial of raltitrexed and radiotherapy as preoperative adjunctive treatment suggest that the recommended dose may be higher than 2.5 mg/m2, as none of the 3 patients entered at this dose level experienced DLT [21]. One of two patients entered at a dose level of 3.0 mg/m2 has had a DLT. A further phase I study will determine the recommended dose of raltitrexed in combination with radiotherapy in patients with inoperable/advanced rectal cancer [22]. The MTD has not yet been determined. No DLT was observed at a raltitrexed dose of 2.0 mg/m2 and only one of six patients experienced DLT (diarrhoea, pancytopenia and pyrexia) at a dose of 2.5 mg/m2. Patients are currently being recruited to 3.0 mg/m2; neither of the two patients recruited, to date, to this dose level has experienced DLT [22]. The question of whether post- or preoperative chemoradiation treatment is optimum for patients with operable rectal cancer should be resolved by the ongoing NSABP R0-3 [23] and MRC CR07 trials which will compare post- and preoperative regimens of radiotherapy combined with 5-FU + LV. The recommended dose of raltitrexed in combination with postoperative radiotherapy for the treatment of patients with rectal cancer is 2.6 mg/m2. Given the manageable toxicity, convenient administration profile and the radiosensitisation properties of raltitrexed, this combination represents a promising therapeutic option for patients with rectal cancer. A phase II study of raltitrexed 2.6 mg/m2 in combination with pelvic radiotherapy is ongoing and will further evaluate the tolerability and efficacy of such chemoradiation in this setting.

Acknowledgements The authors would like to acknowledge Astra Zeneca for providing a grant for this research. We would like to thank our surgical colleagues who kindly referred their patients to us for this study, including Mr David Sellu and Mr John Spencer.

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Received 27 March 2000; accepted 16 June 2000. „ , D r T Price ^ ^ " D e p a r t m e n t o f Clinical Oncology imperical College School of Medicine Hammersmith Hospital D u Ca ne Road London W12 0NN UK E-mail: [email protected]