Helical tomotherapy with concurrent capecitabine for the treatment of inoperable pancreatic cancer

Surgical resection is the standard treatment for localized non-metastatic pancreatic cancer. Data from the Surveillance Epidemiology and End Results (SEER) registry indicate that only about 10% of cases are able to undergo surgery with curative intent, and only a very small number of those are cured because of the high incidence of local relapse and early metastases [1]. Many clinical trials have been carried out using chemotherapy with or without radiation therapy following curative surgical resection, with the aim of preventing local and distant recurrence. With the exception of gemcitabine, neither chemotherapy nor radiation improved survival [2]. For those with locally advanced unresectable or metastatic disease, systemic chemotherapy remains the principal means of improving survival or alleviating cancer-related symptoms

The radiation-sensitive structures in the upper abdomen (small intestine, stomach, kidneys, liver, and spinal cord), prevent conventional radiation therapy to the pancreas or to the pancreatic bed from delivering adequate doses, and irradiation is usually accompanied by severe gastrointestinal intolerance [3]. This may explain in part the absence of survival benefit in patients with locally advanced pancreatic cancer who receive radiation therapy alone. However, 5-FU-based concurrent chemoradiation yields modest survival benefits in patients with locally advanced unresectable pancreatic cancer [4, 5]. Despite these findings, survival from pancreatic cancer is still poor, with approximately 23% of patients alive 12 months following diagnosis, and 5% alive at 5 years [1]. New radiation techniques including intensity modulated radiation therapy (IMRT), image guided radiation therapy (IGRT) and stereotactic radiosurgery make it possible to deliver optimally high doses to the target volume with minimal effect on adjacent radiosensitive tissues [6, 7]. Helical tomotherapy is a sophisticated image-guided IMRT based on the ring gantry concept, employing a combination of a megavoltage CT scanner and a linear accelerator [8, 9]. Capecitabine, a prodrug of 5-FU, is absorbed inert from the gastrointestinal tract and selectively metabolized to 5-FU in tumor cells. This selective conversion achieves higher levels of 5-FU in the tumor cells than can be obtained by intravenous administration of 5-FU. Additionally, radiation can magnify the tumor selectivity of capecitabine by upregulating thymidine phosphorylase in the tumor cells [10]. Capecitabine also acts as a radiation sensitizer by disturbing tumor cell DNA synthesis [11].

In this paper, we report our experience of concurrent administration of capecitabine with helical tomotherapy in patients with inoperable or recurrent pancreatic cancer. We achieved a highly conformal distribution of radiation doses and minimal treatment-related toxicities with excellent target volume responses.

The majority of pancreatic cancer patients have advanced disease at the time of diagnosis due to a lack of symptoms and signs. Without treatment, mean survival time is 4-6 months and overall 5-year survival remains less than 5%. [14]. The only curative option is surgery, but only 10-20% of patients have tumors appropriate for radical resection [15]. Advanced pancreatic cancer is generally incurable and all therapies have significant limitations. The response to systemic chemotherapy is poor, with an approximately 20% response rate. The conventional radiation dose to the tumor volume is not large enough to cure patients because pancreatic tumors move markedly as patients breathe, and are surrounded by the duodenum, which is the dose-limiting organ [16]. Compared with chemotherapy alone or radiotherapy alone, chemoradiotherapy prolongs median survival somewhat, to approximately 9-12 months, in those with locally advanced unresectable disease [5].

Helical tomotherapy, a new radiotherapy system, is a helical IMRT with integrated CT imaging, offering highly conformal radiation with normal tissue sparing. The basis of image guidance is utilizing daily images gained in the treatment position in order to visualize daily organ variations and setup errors [17–19]. The radiation is discharged as a fan beam by a linear accelerator mounted on a turning gantry and is adjusted by a rapid pneumatically driven binary slit collimator [20]. The speed of gantry rotation and table movement is uniform for the entire fraction. Hence helical tomotherapy can provide significant conformal dose distributions at numerous locations [21–24].

Helical tomotherapy can treat multiple lesions more rapidly than conventional radiotherapy, for which multiple target points are necessary [20]. Moreover it is an ideal device for delivering multifocal, high-dose radiation without a significant increase in toxicity [9, 25]. Thus it allows us to treat patients with multiple targets including metastatic lesions.

The ideal concurrent chemotherapeutic agent in the therapy of pancreatic cancer should have both a systemic effect and radiosensitizing properties [16]. Capecitabine has a pronounced radiosensitizing effect on tumor cells such that DNA strand breakage induced by radiation is more difficult to repair [11]. The regimen described here takes advantage of the tumor-selective ability of capecitabine to enhance radiation effects within the tumor but not in the surrounding normal tissues. This can be ascribed to a higher 5-FU concentration in tumor cells and the induction of thymidine phosphorylase by the irradiation [10]. Also, the use of capecitabine is attractive because it is absorbed as an inert drug, causing little direct toxicity in the gastrointestinal tract.

Ben-Josef et al [3] treated 15 patients with unresectable or recurrent pancreatic cancer with IMRT and concurrent capecitabine. In that study, the regimen was well tolerated without significant toxicities, and efficacy was encouraging.

Another basis for offering radiotherapy to patients with pancreatic cancer is palliation of symptoms due to local invasion, such as biliary and gastrointestinal obstruction [26]. The drawbacks of radiotherapy include the acute and chronic toxicities of radiotherapy, particularly when the indication is palliation. Because of its ability to restrict the dose to normal organs and minimize radiation toxicities, helical tomotherapy may be an ideal palliative option for challenging cases of pancreatic cancer [27].

In our study, the overall in-field tumor response rate was 42.3%. Previous studies have reported 10-50% response rates for locally advanced pancreatic cancer with chemoradiotherapy [28–32]. The high response rate in our study is due to in-field assessment of responses. Considering the advanced stage of our patients, the in-field response rate is encouraging. It may be possible to increase this response rate by increasing the dose of capecitabine.

It may be noted that helical tomotherapy with concurrent capecitabine yielded excellent disease control within the radiation field, with an in-field disease control rate of essentially 100%. This could be thought to be a significant therapeutic benefit.

Median overall survival after tomotherapy was only 6.5 months. This was because of advanced stages of our study population (tumor stages III or IV). Our study included patients with locally advanced disease, local relapse following complete resection, and metastases.

Patients who had locally advanced disease without metastasis or a previous history of chemotherapy showed a tendency to survive longer than the others (12.55 versus 4.4 months) after tomotherpy. In our opinion, tomotherapy with concurrent capecitabine should be the first option for inoperable pancreatic cancer, especially in patients without metastases or a previous history of chemotherapy.

Although our patients were elderly, with a median age of 64, treatment was well tolerated. The majority of treatment-related toxicities were mild and transient. Only grade 1/2 fatigue, nausea and hand-foot syndrome developed, and they subsided with symptomatic care and without prematurely stopping radiotherapy. There was no direct treatment-related grade 3/4 toxicity or death. Therefore helical tomotherapy is a safe option in the treatment of advanced pancreatic cancer.

This study had several limitations. First, the number of cases was low. Second, the heterogeneity of the study population made direct comparison with other studies difficult. Third, long term treatment effects and late toxicities remain to be evaluated because the median follow-up time in our study was relatively short.

Although there was no in-field progression during the observation period, out-field progression occurred in seven patients. This observation provides a rationale for follow-up systemic chemotherapy after tomotherapy to prevent or delay out-field progression. Hence, subsequent chemotherapy such as gemcitabine alone or erlotinib combined with gemcitabine should be performed in eligible patients [33, 34].

There are only two examples of the clinical application of helical tomotherapy for locally advanced pancreatic cancer [35]. To the best of our knowledge, this is first comprehensive analysis of the clinical application of helical tomotherapy for a group of inoperable or recurrent pancreatic cancers.

Our study demonstrates that helical tomotherapy with concurrent capecitabine is a feasible and safe option for locally advanced unresectable or metastatic pancreatic cancer. Our preliminary data yielded a high local control rate. Because of its ability to irradiate multiple targets simultaneously, helical tomotherapy could be an ideal palliative option for challenging cases of pancreatic cancer with metastases. Further large scale clinical trials are needed to verify the efficacy and safety of helical tomotherapy with concurrent capecitabine for treating advanced pancreatic cancer. Also, careful selection of those patients that stand to benefit from this regimen is needed.