Chemoradiation for Ductal Pancreatic Carcinoma: Principles of Combining Chemotherapy with Radiation, Definition of Target Volume and Radiation Dose

Ralf Wilkowski1, Martin Thoma1, Helmut Weingandt1, Eckhart Dühmke1, Volker Heinemann2

1Clinic for Radiation Oncology and 2Medical Clinic III, LMU University Hospital Grosshadern. Munich, Germany

*Corresponding Author:
Martin Thoma
Klinik und Poliklinik für Strahlentherapie und
Radioonkologie
Klinikum Großhadern der LMU
Marchioninistraße 15
81377 München
Germany
Phone: +49-89.7095.3770
Fax: +49-89.7095.6770
E-mail: [email protected]

Received January 16th, 2005 - Accepted March 10th, 2005

 
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Abstract

Review of the role of chemoradio-therapy in the treatment of locally advanced pancreatic cancer with a specific focus on the technical feasibility and the integration of chemoradiotherapy into multimodal treatment concepts. Combined chemoradiotherapy of pancreatic cancer is a safe treatment with an acceptable profile of side effects when applied with modern planning and radiation techniques as well as considering tissue tolerance. Conventionally fractionated radiation regimens with total doses of 45-50 Gy and small-volume boost radiation with 5.4 Gy have found the greatest acceptance. Locoregional lymphatic drainage should be included in the planning of target volumes because the risk of tumor involvement and local or loco-regional recurrence is high. Up to now, 5-fluorouracil has been considered the "standard" agent for concurrent chemoradiotherapy. The role of gemcitabine given concurrently with radiation has not yet been defined, since high local efficacy may also be accompanied by enhanced toxicities. In addition, no dose or administration form has been determined to be “standard” up to now. The focus of presently ongoing research is to define an effective and feasible regimen of concurrent chemoradiotherapy. While preliminary results indicate promising results using gemcitabine-based chemoradio-therapy, reliable data derived from mature phase III trials are greatly needed. Intensity-modulated radiotherapy has been developed to improve target-specific radiation and to reduce organ toxicity. Its clinical relevance still needs to be defined.

Keywords

Antineoplastic Combined, Chemotherapy Protocols; Combined Modality, Therapy; Drug Therapy; Pancreatic, Neoplasms; Radiotherapy

Abbreviations

5-FU: 5-fluorouracil; CRT:, chemoradiotherapy; CTV: clinical target, volume; EBRT: External Beam Radiation, Therapy; EORTC: European Organization for, the Research and Treatment of Cancer;, ESPAC: European Study Group for, Pancreatic Cancer; FAM: 5-fluorouracil,, adriamycin/doxorubicin, mitomycin C;, GITSG: Gastrointestinal Tumor Study Group;, HR: hazard ratio; ICRU: International, Commission on Radiation Units and, Measurements; IMRT: intensity-modulated, radiotherapy; IORT: intraoperative radiation, therapy; NTCP: normal tissue complication, rate; SMF: streptozotocin, mitomycin C, 5-, fluorouracil; UICC: International Union, Against Cancer

INTRODUCTION

Radiotherapy plays an important role in the, treatment of non-metastatic pancreatic cancer, [1, 2]. Due to the near absence of early, symptoms and the late appearance of mostly, uncharacteristic complaints, only about 20%, of tumors are diagnosed at a surgically, resectable stage [3]. Adjuvant chemoradiotherapy, is applied to reduce the very high risk, of local recurrence. Neo-adjuvant radio- or, chemoradio-therapy aims to improve, resectability [4]. A conclusive assessment of, whether this will also improve the survival, rate is not yet possible.

About 20-40% of patients present with a, locally advanced tumor which is not curable, by resection. The aim of primary radio-, (chemo-)therapy in this situation is to achieve, a local response with the aim of preventing local tumor complications (e.g. pain,, hemorrhage or stenoses of the choledochus or, the duodenum) and perhaps achieving, secondary resectability through downstaging, or downsizing [5, 6].

Since pancreatic cancer appears to be a, systemic disease early on, about 40-70% of, patients already present with distant, metastases at primary diagnosis. In this, situation, radiotherapy can be applied for the, local palliation of tumor complications such, as hemorrhage or pain.

This review aims to provide an overall view, of the technical administration of radiotherapy, and explain how it can be included in, multimodal therapy regimens.

Systemic Chemotherapy

There is no common agreement that locally, advanced pancreatic cancer patients should, either receive radiochemotherapy or, chemotherapy alone. A retrospective cohort, study performed on 1,696 patients with, locally advanced pancreatic cancer,, documented by means of surveillance,, epidemiology, and end result medicare, database indicated that only 44% of patients, received some form of cancer-directed, treatment. The risk of death was calculated, with logistic regression depending on the, administered therapy modality. The hazard, ratio (HR) was the lowest when, chemoradiotherapy was applied (HR: 0.44;, 95%CI: 0.39-0.50) as opposed to radiation, alone (HR: 0.68; 95% CI: 0.58-0.79) or, chemotherapy alone (HR: 0.66; 95% CI: 0.54-, 0.81) [7].

With regard to systemic chemotherapy, the, standard therapy was5-fluorouracil (5-FU), administered for an extended period. More, aggressive combination therapies such as, FAM (5-FU, adriamycin/doxorubicin,, mitomycin C), SMF (streptozotocin,, mitomycin C, 5-FU), or the Mallinson, regimen (5-FU, cyclophosphamide,, methotrexat, and vincristin) with increased, toxicity, did not result in an improvement in, survival time [8, 9]. Even newer agents, such as paclitaxel, docetaxel, irinotecan, topotecan, or oxaliplatin, could not be established as an, effective treatment for pancreatic cancer [10]., A modest improvement in treatment efficacy, could only be shown after the introduction of, the pyrimidine analogue gemcitabine [11],, which is characterized not only by a positive, effect on clinical benefit response but also by, an acceptable risk of side effects., Gemcitabine is presently regarded as a, standard medication in advanced pancreatic, cancer. The combination of gemcitabine with, cisplatin or 5-FU improved response rates and, time to progression [12]. Preclinical data, indicated that gemcitabine acts as an effective, radiation sensitizing agent which thereby, allowed its inclusion into simultaneous, chemoradiotherapy protocols [13, 14].

Radiotherapy

Since pancreatic cancer is only moderately, sensitive to radiation, doses of 70 Gy and, higher are recommended for radiotherapy, when given without chemotherapy [15]., However, the radiosensitivity of adjacent, organs such as the liver, kidneys, stomach,, and small intestine as well as the spinal cord,, considerably limits the option of, administering such doses percutaneously. A, high rate of side effects and complications are, to be expected. Furthermore, radiotherapy, alone did not improve the overall survival rate, [16].

Intraoperative radiation therapy (IORT) with, fast electrons offers the opportunity of, administering comparatively high radiation, doses directly to the tumor or to the tumor, bed, while protecting the adjacent organs at, risk. With a moderate rate of side effects,, IORT doses of 25-40 Gy can achieve local, tumor- or pain-control [17, 18]. However,, IORT alone did not improve the overall, survival rate.

IORT can also be used as a boost in, combination with external radio- (chemo-), therapy [19, 20, 21]. Thereby, it is possible to, reduce the percutaneous radiation dose to 40-, 50 Gy while maintaining improved loca tumor control. While a definite survival, advantage has not been proven [22, 23],, particularly high total doses of IORT (IORT, 20.0 Gy, external beam radiation therapy, (EBRT) up to 50.0 Gy), have induced, considerable complications, specifically with, regard to hemorrhage [24]. Other reasons, against a more widespread use of IORT lie in, the technical and logistical complexity of this, procedure. In addition, there are, radiobiological objections to be raised., Because of the interval of four to six weeks,, which pass between IORT and external, radiotherapy as a rule, accelerated, repopulation may reduce the antitumor effect, [25].

Concurrent Radiochemotherapy

In the 1960s, the Mayo Clinic had already, documented the improved efficacy of, combined chemoradiotherapy in a, randomized study. This trial indicated an, improved survival rate of 10.4 months in, patients treated with 5-FU-based, chemoradiotherapy (35 Gy in 4 weeks) as, compared to 6.3 months observed in the, group with radiotherapy only [16]. These, results were confirmed in further randomized, studies carried out in the 1980s by the, Gastrointestinal Tumor Study Group, (GITSG). In unresectable patients,, radiotherapy (40.0 or 60.0 Gy) in combination with 5-FU resulted in a significantly, improved survival rate (9.6 and 11.4 months,, respectively) as compared to 5.2 months after, radiotherapy only (60.0 Gy) [26]. A further, GITSG study demonstrated a significantly, longer survival time for radiotherapy (54.0, Gy) followed by SMF chemotherapy as, compared to SMF chemotherapy alone (42, versus 32 weeks, 1-year survival 41% vs., 19%) [27]. At the same time, Klaassen et al., saw no advantage in using combined 5-FU, based chemoradiotherapy in comparison to, chemotherapy with 5-FU alone (median, survival: 8.3 vs. 8.2 months) [28]. Table 1, presents the randomized phase III studies on, radiochemotherapy of locally advanced, pancreatic cancer.

Table

The postoperative and adjuvant treatment, after curative resection of a pancreatic, carcinoma will be discussed. Previous studies, of the GITSG show a significant survival, benefit when combined chemoradiotherapy is, ued. However, these data have not been, confirmed in any major European studies. An, European Organization for the Research and, Treatment of Cancer (EORTC) study by, Klinkenbijl et al. showed an improved, survival rate of 24.5 months in patients with, postoperative chemoradiotherapy as, compared to 19.0 months in the control group, [29]. However, this difference was not, significant. The data of the European Study, Group for Pancreatic Cancer (ESPAC-1) study publicized in 2001, showed a worsening, of the survival rate under radiotherapy as, compared to chemotherapy [30]., Among the chemotherapeutic agents used, concurrently with radiation, 5-FU has long, been regarded as standard medication,, because its efficacy and tolerability have been, well-documented and confirmed by numerous, studies.

Concurrent Chemoradiotherapy with, Gemcitabine

Even though several phase I and II studies, have investigated gemcitabine-based, radiochemotherapy, it has not yet been, possible to establish a defined regimen either, with respect to the dose and administration of, gemcitabine or with regard to the treatment, volume, fractionation and cumulative dose of, radiation. The most common form of, administration has been a weekly infusion of, 30 minutes duration; at the same time, a, twice-weekly application [31] or the, application of a 24-hour continuous infusion, [32] have also been investigated. Weekly, doses of up to 600 mg/m2 have been used, when conventional single radiation doses, were administered. In addition, the more toxic, combinations with 5-FU, cisplatin, or, mitomycin C have also been described (Table 2).

Table

Concurrent radiotherapy has been most, frequently administered in conventional, fractionation with total doses of 40.0 to 50.4, Gy, whereas the use of hypofractionated (3x8, Gy) [33], accelerated (10x3 Gy) [34] or, hyperfractionated regimens is also reported, [35].

Therefore, it has to be emphasized that, in, concurrent chemoradiotherapy, either the dose, of gemcitabine or the radiation dose needs to, be reduced. Otherwise, severe gastrointestinal, complications such as ulceration or, hemorrhage may be encountered, specifically, when using fractions greater than 2.2-2.4 Gy, [33, 34]. Increasing the weekly gemcitabine, dose may also cause considerable gastrointestinal side effects. For weekly doses, of up to 300 mg/m2, only moderate, gastrointestinal complaints such as vomiting, and nausea have been reported, rising, considerably when the gemcitabine dose was, increased to weekly doses equal to 400 mg/m2, or more [36, 37,38].

It is known from the previous administration, of gemcitabine concurrent with the irradiation, of the lung region that pulmonary toxicity, depends greatly on the irradiated volume. As, a result, Scalliet et al. reported 6 severe acute, and 4 severe long-term complications in 8, treated patients with 3 therapy-related deaths, [39]. In subsequent studies [40, 41] which, strictly limit the target volume, lower, toxicities were observed. Therefore, it can be, concluded that the target volume is a critical, parameter in the irradiation of the upper, abdominal region when administered, concurrently with gemcitabine. However, no, studies are available for comparison in this, regard. Most of the authors used a high target, volume including loco-regional lymph, pathways. In view of the very different dose, and fractionation concepts, no comparable, toxicities can be defined regarding the target, volume.

Patients treated in our institution received, concurrent chemoradiotherapy with 50.0 Gy, applied to the macroscopic tumor and 45.0 Gy, to the locoregional lymph nodes in 25, fractions. Concurrent chemotherapy was, administered giving gemcitabine 300 mg/m2, and cisplatin 30 mg/m2 on days 1, 8, 22, and, 29. The side effects of the treatment were, limited mainly to the changes in blood tests., Whereas no serious gastrointestinal toxicities, were observed, leukopenia Grade III and IV, were seen in 60% and thrombopenia Grade III, and IV in 51% of the patients. In 45 patients,, a remission rate of 69% (9 complete and 22, partial remissions) was observed. In 30% of, the primarily unresectable patients, it was, possible to carry out a secondary R0 resection, [6]. However, up to the present time it still, needs to be assessed as to whether this locally, effective treatment also improved overall, survival.

Improving Systemic Efficacy of, Concurrent Radio-Chemotherapy

Even with locally more intensive treatment, (also including IORT), no improvement in, overall survival rates has been achieved [42]., This is possibly explained by the early, systemic dissemination of pancreatic cancer, which ultimately determines the prognosis., Following this rationale, McGinn et al., applied gemcitabine at its full cytotoxic dose, (1,000 mg/m2 weekly) in a clinical trial., Assuming that the major effect of, radiotherapy is achieved by control of the, primary tumor and, in an effort to avoid, increased toxicity, radiation was limited to the gross tumor only, leaving out the locoregional, lymphatic drainage [43]. Keeping the duration, of radiation constant at three weeks,, individual fractionation was increased. This, allowed the establishment of the application, of 36 Gy in 2.4 Gy fractions as a tolerable, regimen. The maximum dose level of 42 Gy, given in 2.8 Gy fractions, which is roughly, equivalent to a total dose of 50.4 Gy applied, with a 1.8 Gy fractionation, proved to be too, toxic. The response rate to this therapy was, 18% (on completion of the therapy) and 33%, following additional systemic chemotherapy., Average survival rates were 11.6 months and, were therefore comparable with 5-FU based, chemoradiotherapy. Despite the low volume of irradiation, the rate of regional lymph node, recurrence was low (3/37 patients). Local, tumor progression occurred in 7 of 37, patients. The progression of the disease was, influenced mainly by the metastases (in 25 of, 37 patients). The authors therefore concluded, that low volume radiotherapy has not resulted, in excess locoregional failure with intensive, systemic therapy, especially when considering, the potential toxicity of the treatment.

Blackstock et al. conducted a phase I study, where gemcitabine was given twice weekly, together with concurrent radiotherapy (45.0, Gy large volume, 5.4 Gy boost). The, maximum tolerated dose was 40 mg/m2 of, gemcitabine. The median survival rate of 11, months is, however, comparable to other, chemoradiotherapy regimens.

Even if it is very problematic to draw, conclusions as to the survival without, available phase III studies, it may, nevertheless be concluded that, regarding the, survival times, a single superior regimen of, gemcitabine-based chemoradiotherapy has not, been defined so far.

Local Spread of the Tumor

Pancreatic cancer infiltrates the adjacent, peripancreatic or retroperitoneal tissue, already at an early stage. In addition, there is, frequently perineural infiltration as well as an, invasion of local lymphatic vessels.

The local lymphatic drain from the pancreas, consists of a peripancreatic first node and a, perivascular second node along the A., mesenterica sup, A. gastroduodenalis, A., hepatica communis, as well as the A. lienalis, and truncus coeliacus. Because of their close, proximity, the paraaortal and paracaval lymph, nodes as well as the lymph nodes of the vena, portae hepatis are also frequently affected, [44]. According to the International Union, Against Cancer (UICC) classification, the, peripancreatic lymph nodes are divided, according to their location into superior and, inferior (above or below the head or body of, the pancreas, respectively), anterior (anterior, pancreaticoduodenal, pyloric and proximal, mesenteric lymph nodes) and posterior (posterior pancreaticoduodenal lymph nodes), as well as into lymph nodes along the ductus, choledochus and proximal mesenteric lymph, nodes, lienal nodes (for tumors of the, pancreas corpus and cauda), and also celiac, lymph nodes (for tumors of the pancreas, head).

The risk of invasion of the locoregional, lymph nodes ranges between 76% and 83%, according to analyses of histological, specimens carried out in Japan [45, 46]. In, 15-20% of cases, an affection of the, paraaortal lymph nodes is also to be expected, [44, 45]. However, in pre-operative, diagnoses, the suspicion of lymph node, involvement was only observed in about onethird, of all cases.

The high risk of lymph node metastasis, indicates that there might be the necessity of, extending the clinical target volume beyond, the macroscopic tumor to the regional lymph, nodes, even though there are no comparative, studies available on the risk of a lymph node, relapse following small volume radiation., It should be mentioned in this regard that, in, patients treated with IORT after resection, (partly complemented with external, chemoradiotherapy), local recurrences, occurred in 30-50% [18, 19, 47]. These can, most likely be evaluated as local lymph node, recurrences on the basis of the high dose, administered with IORT in the tumor bed.

Definition of Target Volume and Radiation, Treatment Planning

A 3-dimensional conformal radiation, treatment plan is required to guarantee the, optimal protection of the adjacent, radiosensitive organs. Positioning and, immobilization aids are used to ensure stable, and reproducible positioning despite raised, arms in order to facilitate lateral radiation, angles and the resulting lordosis of the lumbar, spine.

In correspondence with the rapid lymphatic, spread of the pancreatic tumor, loco-regional, radiation (CTV-II) should include the, superior, inferior, anterior and posterior, pancreaticoduodenal, pyloric, celiac, and proximal mesenteric lymph nodes as well as, those of the ductus choledochus and the, paraaortic lymph nodes in the region. In the, case of a carcinoma of the pancreatic cauda,, or respectively body and cauda, the superior,, inferior, posterior pancreaticoduodenal,, proximal mesenteric, and lienal lymph nodes, are to be included. It is rare for the retrocrural, and retrocaval lymph nodes to be affected., For that reason, there is no need for them to, be included as standard in the target volume., Investigations of organ motility and, respiratory movement showed a considerable, positioning variability of the organs in the, upper abdomen. The positioning variability at, the pancreas which is dependent on, respiration occurs mainly in the cranio-caudal, direction (up to 2.4 cm) [48]. It is less, distinctive in the lateral and anterior-posterior, direction. Positioning variabilities, independent of respiratory motion have been, seen especially on the pancreatic body and, tail, as well as on the A. mesenterica sup., These are associated with the peristalsis, and, the filling of the stomach and the intestines,, respectively. [49]. Because of respiratory, movement, intestinal motility, and variability, in the positioning, a safety margin of 2-3 cm, should be added to the clinical target volume, (CTV II).

The craniocaudal range of the irradiation, fields typically extends from the level of the, porta hepatis to the level of the junction of, the V. mesenterica inferior. The lateral and ventrodorsal extent of the field has to be, determined on the basis of pretherapeutic CT, or MR imaging. Limited irradiation of the, tumor or a boost treatment should encompass, the macroscopic pancreatic tumor plus a, safety margin of about 1 cm. With the help of, dose volume histograms, the dose in adjacent, organs at risk (liver, kidneys, spinal cord), should be assessed in order to prevent, exceeding tolerance levels (Figure 1)., According to Emami et al. [50], the tolerance, dose of TD5/5 for the liver is 50 Gy, 35 Gy,, 30 Gy for 1/3, 2/3 or 3/3 of the organ volume,, respectively. Newer investigations, using, mathematical models to estimate the normal, tissue complication rate (NTCP), indicate a, higher tolerance of the liver tissue, at least in, the irradiation of partial volumes [51]., Dawson et al. [52] indicated a 5% risk of, radiogenic liver damage at 90 Gy, 47 Gy or, 31 Gy for 1/3, 2/3 or 3/3 of the liver volume,, respectively. On the other hand, pancreatic, cancer patients frequently have prior damage, to the liver parenchyma as a consequence of, cholestasis and perfusion deficits. The, tolerance of the liver may also be further, reduced due to concurrent chemotherapy. For, that reason, we reduce liver exposure to a, maximum of 12.5 Gy in 75%, 25 Gy in 50%,, and 37.5 Gy in 25% of the liver volume,, respectively, in our institution. Temporary, radiogenic hepatosis occurred only, occasionally (less than 5%) in our patients,, thus keeping within these limits. We have not, seen long-lasting liver function damages., For the kidneys, Emami et al. stated tolerance, doses of TD5/5 of 50 Gy, 30 Gy, or 23 Gy for, 1/3, 2/3, or 3/3 of the organ volume,, respectively. Even if the risk of clinical, nephropathy seems to be limited by a partial, exposure to 25-40 Gy, it is nonetheless, possible that a major reduction of the, creatinine clearance may be induced [53]., Concurrent chemotherapy, specifically the use, of cisplatin and other nephrotoxic agents (e.g., aminoglycoside antibiotics) can significantly, reduce the tolerance level of the kidneys [54]., For this reason, we take care not to expose, 30% of a kidney to more than 20 Gy. No, radiogenic nephropathies were observed in our patients in this regard. In addition, prior to, starting the therapy, kidney clearance should, be checked, if possible for each kidney, separately with an isotope nephrogram in, order to take individual differences in kidney, function into account in planning radiation, treatment.

pancreas-dose-volume-histograms

Figure 1. Dose-volume-histograms of the tumor-region (PTV I) with regional lymphatic pathways (PTV II) and relevant organs at risk (SC = spinal cord).

It is generally no problem to keep the, tolerance dose of the spinal cord to about 40-, 50 Gy through the use of multi-field techniques. In order to keep acute and late, gastrointestinal reactions to the minimum, possible, maximum protection of the small, intestine should be aimed at in planning, radiation treatment. Specifically, in the case, of pre-existing adhesions (e.g. from previous, operations), reduced intestinal motility can, result in a higher exposure of individual, intestinal sections with an associated higher, risk of complications. As a basic principle, a planning CT (slice thickness between 0.5 and, 0.8 mm) with sufficient intestinal contrast, should form the basis for planning radiation, treatment. The use of i.v.-contrast can be, helpful in exactly demarcating the tumor and, visualizing vessels and lymph node regions., Dependent on the range of the target volume, and the relation to the anatomical position of, the kidneys and the liver, the main technique, used is a non-orthogonal 3-4 field technique, with one ventral, two lateral, and possibly, also an additional dorsal irradiation field, (Figure 2). Under unfavorable anatomical, conditions, significantly more fields may be, required from different irradiation angles (e.g., using the half-field asymmetric technique)., The dose should be specified in accordance, with ICRU-50 (International Commission on, Radiation Units and Measurements) and its, requirements regarding the homogeneity of, dose distribution should also be fulfilled., With the same total number of fractions, a, “field-in-field” irradiation technique can, achieve an increase in the individual dose in, CTV I, while maintaining the target dose in, CTV II. The central volume comprises CTV I,, and the peripheral volume CTV II. Because of, the small partial dose proportion of the central, field, the dose within this volume can be, modified. The dose in the ICRU reference, point is defined commensurate with the target, dose in CTV I.

pancreas-dr-four-field-treatment

Figure 2. DRR-images showing a four-field-treatment-plan for a patient with cancer of the pancreatic head (see Figure 3). Via the dorsal supplementary-field a higher dose is applied in the tumor-region. In this area 2.0 Gy are given per fraction whereas the loco-regional lymph-nodes received 1.8 Gy. A total of 50.0, respectively. 45.0 Gy were administered. Green lines: open field which will be modeled individually with the multi-leaf-collimator (yellow border). (Turquoise triangle: use of a wedge filter for dose optimization.)

In the Munich study (a phase II study to, compare chemoradiotherapy using, gemcitabine/cisplatin with chemoradiotherapy, using 5-FU in patients with locally advanced, unresectable pancreatic carcinoma) (doses of, 50.0 Gy in CTV I and 45.0 Gy in CTV II are, aimed for. In 25 individual fractions over 5, weeks, a dose of 2.0 Gy is defined as the, ICRU reference point; with field weighting,, an isodose of at least 95% covers the area of, CTV I, whereas, as a minimum requirement,, CTV II is included in the 85% isodose. An, irradiation which conforms to ICRU-50 is, thus administered in CTV I. The dose of CTV, II can only be defined in line with the, surrounding isodose. In line with IMRT, radiation treatment planning, compliance with ICRU-50 criteria regarding dose homogeneity, is aimed for. Strictly speaking, this dose, specification (of CTV II) does not comply, with ICRU-50 criteria, but it has proven its, practical value in the clinical routine of, radiation treatment planning. For clarification,, Figure 3 shows a radiation treatment plan, which has been drawn up on the basis of this, dose regimen.

pancreas-3d-conformal-treatment

Figure 3. 3D-conformal treatment planning in a patient with unresectable cancer of the pancreatic head. Horizontal slize in upper field boundary (a.), central ray level (b.) and in lower field boundary (c.). Gross tumor volume (enclosed by the 100%-isodose) and tumor with locoregional lymph nodes (enclosed by the 90%-isodose) were marked as treatment volumes. Radiotherapy is administered with 4-field arrangement.

Future Prospects: Intensity-Modulated, Radiotherapy (IMRT)

IMRT and inverse radiation treatment, planning may open new opportunities to, apply higher and more homogenous doses, within the tumor region while, at the same, time achieving a lower exposure in adjacent, critical structures, especially in the small, intestine [55]. A first phase I study using, concurrent gemcitabine (350 mg/m2) as a, radiosensitizer and escalating doses of IMRT, yielded disappointing results [56]. Doselimiting, toxicities occurred already at the first, level (33 Gy in 11 fractions) and were also, observed after the gemcitabine dose had been, reduced to 250 mg/m2.

At the present time, it is not yet possible to, predict whether the expectations which IMRT, had raised will be fulfilled in the radiation, therapy of pancreatic cancer. The need to, define the CTV liberally because of the, variability in positioning and the difficulty in, defining the macroscopic tumor region speaks, against the advantages of IMRT, namely, that, high irradiation doses will be administered in, a closely defined region.

Conclusions

It can be concluded that, with modern, techniques in the planning and application of, radiation treatment as well as keeping the, dose tolerances both in radio- and chemotherapy,, chemoradiotherapy of pancreatic, carcinomas can be administered safely and, with an acceptable level of tolerance.

Even if there is no comparative data available,, the high risk of involvement of the locoregional, lymph nodes speaks in favor of their inclusion in the clinical target volume. It is, common to use conventional fractionation, regimens with a total dose of 45.0-50.4 Gy in, CTV II, possibly supplemented with a small, volume boost in the tumor region of e.g. 5.4, Gy. With the help of IMRT, further organ, protection (especially of the small intestine), might be achieved, even though there is no, evidence of this at present.

With respect to concurrent chemotherapy, 5-, FU may still be regarded as the standard, medication, with a dose of 200-350 mg/m2, per irradiation day. Meanwhile, promising, data are available regarding gemcitabinebased, chemoradiotherapy. However, the, optimal dose and application of this, radiosensitizing agent as well as an additional, combination partner still need to be defined.

References

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