Reirradiation and hyperthermia in rectal ... - Wiley Online Library

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3 Department of Statistics, Erasmus MC–Daniel den Hoed Cancer Center, ... Netherlands; Fax: (011) 31 104391022; E-mail: [email protected]

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Reirradiation and Hyperthermia in Rectal Carcinoma A Retrospective Study on Palliative Effect

Jorine H. M. Juffermans, M.D.1 Patrick E. J. Hanssens, M.D.2 Wim L. J. van Putten, M.Sc.3 Gerard C. van Rhoon, Ph.D.1 Jacoba van der Zee, M.D., Ph.D.1 1

Department of Radiation Oncology, Hyperthermia Unit, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

2

Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Tilburg, The Netherlands.

3

Department of Statistics, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

BACKGROUND. The objective of this study was to evaluate the palliative effect of reirradiation and hyperthermia in patients with unresectable, recurrent colorectal carcinoma. METHODS. The medical records of 54 patients with unresectable, recurrent colorectal carcinoma that caused pain and who were treated with reirradiation and hyperthermia, were evaluated retrospectively. Previous radiotherapy was given up to a total dose ranging from 25–70 grays (Gy). The median interval between prior radiotherapy and reirradiation was 22 months (range, 4 –97 months). The total reirradiation dose varied from 24 Gy to 32 Gy given in fractions of 4 Gy twice weekly. Three or four hyperthermia treatments were given once weekly. Toxicity was registered. The influence of World Health Organization (WHO) performance status, maximum tumor dimension, and time between first radiotherapy and reirradiation on therapeutic outcome was evaluated. The results of this study were compared with published results on patients who received radiotherapy with or without hyperthermia.

RESULTS. Forty-seven patients (87%) completed the planned treatment schedule. The maximum toxicity was Grade 2. All patients were evaluated for palliative effect. The median follow-up was 10 months. A good or complete palliative effect was achieved in 72% of patients for a median duration of 6 months. Patients who had a better WHO performance status, smaller tumors, and a longer interval between first radiotherapy and reirradiation had slightly better outcomes, although none of those parameters reached statistical significance. CONCLUSIONS. The described combined treatment was feasible and well tolerated. Comparison of results from radiotherapy plus hyperthermia with results after radiotherapy alone suggested that additional hyperthermia prolonged the duration of palliation. Firm proof of the contribution of hyperthermia will require performing a Phase III study. Cancer 2003;98:1759 – 66. © 2003 American Cancer Society. KEYWORDS: rectal carcinoma, local recurrence, radiotherapy, reirradiation, hyperthermia, palliation.

C

Address for reprints: Jacoba van der Zee, M.D., Ph.D., Department of Radiation Oncology, Hyperthermia Unit, Erasmus MC Daniel den Hoed Cancer Center, P.O. Box 5201, 3008 AE Rotterdam, The Netherlands; Fax: (011) 31 104391022; E-mail: [email protected] Received January 15, 2003; revision received July 8, 2003; accepted July 22, 2003. © 2003 American Cancer Society DOI 10.1002/cncr.11719

olorectal carcinoma is one of the most common malignancies in the Western world. After primary surgery, a local recurrence is reported to develop in 10 – 60% of patients, depending on tumor stage, distance from the anal verge, and surgical technique. Adjuvant radiotherapy, with or without chemotherapy, results in a substantial reduction of this risk; however, 2–25% of patients still will develop a local recurrence.1– 4 The prognosis is poor for most patients with colorectal carcinoma who have an unresectable local recurrence and who previously underwent surgery and received radiotherapy,5 and the main objective of any further therapy is palliation. Pain has an important negative influence on the quality of life for these patients. When the tumor progresses, it often is difficult to control the pain

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with medication.6 Other therapeutic options are limited. From reirradiation alone—at relatively small doses that still can be applied—little is to be expected. Studies on chemotherapy for patients with recurrent colorectal carcinoma have shown that objective response rates usually are below 40%.7 It is expected that this response rate will be even lower in patients with a previously irradiated pelvis due to the vascular damage that may be induced by ionizing radiation.8 In view of these discouraging prospects, it was decided that, based on the good results we have seen previously from reirradiation combined with hyperthermia in the treatment of patients with breast carcinoma,9 we would attempt a similar palliative regimen of reirradiation and hyperthermia in a group of patients with colorectal carcinoma. To evaluate the palliative effect of this treatment, a retrospective study was performed by analysis of the medical records of 54 patients who were treated with reirradiation and hyperthermia for pain due to recurrent rectal carcinoma. The primary objectives of this evaluation were to establish the feasibility, tolerance, and palliative effect of the combined treatment. A secondary objective was to determine possible prognostic factors for a palliative effect.

TABLE 1 Summary of Previous Radiotherapy and Reirradiation Plus Hyperthermia Total RT dose in Gy (no. of fractions)

No. of HT treatments

Previous RT

Reirradiation

No. of patients

25 (5) 30 (10) 30 (10) 35 (15) 40 (22) 40 (18) 41 (18) 45 (25) 45 (20) 46 (20) 48 (19) 50 (28) 50 (25) 50 (25) 50 (25) 52 (26) 54 (27) 55 (22) 58 (29) 60 (30) 60 (26) 70 (35)

32 28 32 32 32 32 32 32 32 32 32 32 24 28 32 32 32 32 24 24 24 24

1 1 3 1 1 1 2 3 2 1 1 4 3 1 18 1 1 1 1 4 1 2

3

4 1

1

2

3 1 1 1 2 1 2

1 1 4 3 1 2

16 1 1 1

1 4 1 2

MATERIALS AND METHODS Patient and Tumor Characteristics Fifty-four patients with unresectable, recurrent rectal carcinoma that caused pain were treated with reirradiation and deep hyperthermia between 1990 and 2000. Their medical records were evaluated retrospectively. Patient age ranged from 38 –77 years (median age, 63 years). There were 37 males and 17 females. Most patients had a relatively good general condition; 23 patients had World Health Organization (WHO) performance status scores of 0, and 25 patients had WHO scores of 1. Five patients had WHO scores of 2, and 1 patient had a WHO score of 3. Usually, higher WHO scores were due to pain. All primary tumors were adenocarcinoma, and all but one tumor (which was located in the colon) were located in the rectosigmoid. All patients underwent surgery for the primary tumor, usually an abdominal perineal resection (38 patients) or a low anterior resection (14 patients). The original tumors were Duke Stage A in 3 patients, Stage B in 18 patients, Stage C in 24 patients, Stage D in 2 patients, and the stage was unknown in 7 patients. Nineteen patients had been treated with chemotherapy. All patients had been treated previously with radiotherapy. The total dose of the primary radiotherapy was a median of 50 grays (Gy) (range, 25–70 Gy) with a mean fraction size of 2

RT: radiotherapy; Gy: grays; HT: hyperthermia.

Gy (range, 180 –500 centigrays) (Table 1). In one patient, primary radiotherapy was combined with hyperthermia. Forty-six recurrences were located presacrally, including 8 tumors with extension to the perineal region. The remaining recurrent tumors were located elsewhere in the true pelvis. Assessment of resectability was done by surgeons and produced negative results due to tumor extension for each patient who was included. The maximum dimension of the recurrence was a median of 94 mm (range, 30 –172 mm), as measured on computed tomography (CT) scans. In 12 patients, there was evidence of distant metastasis. However, in view of the palliative intention of the combined treatment, routine screening for metastatic disease was not performed. To categorize the intensity of pain, different systems were used between 1990 and 2000. These systems have been converted into a five-point pain scale to classify the intensity of pain as follows: mild, moderate, severe, very severe, and unbearable.10 Severity of pain and pain medication at the start of combined treatment are summarized in Table 2. In 21 patients, the pain was local; in 4 of those

Reirradiation and Hyperthermia in Rectal CA/Juffermans et al. TABLE 2 Pain Score and Pain Medication at the Start of Combined Treatment Pain score Pain medicationa None Step 1 Step 2 Step 3 Step 4

Mild

Moderate

Severe

2 2

4 3 1 3

2 6 3 10

Very severe

Unbearable

1 2 9 2

3 1

a

Step 1: paracetamol, nonsteroidal antiinflammatory drug; Step 2: paracetamol or nonsteroidal antiinflammatory drug plus codein; Step 3: oral morphinomimetics; Step 4: parenteral morphinomimetics.

patients, there was clear evidence of bone invasion. In 33 patients, the pain was radiating to 1 or both legs, indicating nerve invasion or compression.

Radiotherapy The reirradiation schedule used in most patients was 8 ⫻ 4 Gy (41 patients; usually if previous radiotherapy was ⱕ 55 Gy) or 6 Gy ⫻ 4 Gy (11 patients; usually if previous radiotherapy was ⬎ 55 Gy) applied in two fractions per week. Two patients received 7 fractions of 4 Gy (Table 1). Dose specifications and target volume definitions were according to a report from the International Commission on Radiation Units and Measurements.11 Treatment planning was based on CT scans. All macroscopic, local, recurrent disease was included in the reirradiation field with a margin of at least 1 cm. The majority of patients were treated with a minimum of three radiation fields. The interval between primary radiotherapy and reirradiation was a median of 22 months (range, 4 –97 months). The cumulative total dose (primary radiotherapy plus reirradiation) was a median of 82 Gy (range, 57–94 Gy).

Hyperthermia Hyperthermia was applied with the BSD-2000 heating system with a Sigma-60 applicator.12,13 Each treatment was planned to last 60 minutes after an interstitially measured tumor temperature had reached 42 °C, after a maximum 30 minutes of heating time. Without interstitial tumor temperature measurements, the treatment duration was 90 minutes. During treatment, the temperatures in the target volume were increased as high as possible and as homogeneous as possible within the tolerance limits. The patients were instructed carefully to mention any unpleasant sensation suggestive of a hot spot. At the occurrence of a temperature that was too high, either measured or reported by the patient, treatment settings were ad-

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justed depending on the location of the hot spot. The power level was increased to the maximum level tolerated by the patient, following appropriate adjustments of treatment settings. The hyperthermia treatments were given once weekly, 2– 4 hours after a radiation fraction. Twenty-three interstitial catheters for thermometry during hyperthermia were inserted into 14 patients. These catheters were placed intratumorally before the first hyperthermia treatment and remained in situ until after the last hyperthermia treatment or until problems required removal.14 All patients had intraluminal thermometry for power steering during treatment.

Palliative Effect A complete palliative effect was defined as the complete disappearance of pain without any pain medication for at least 1 month. A good palliative effect was defined as either a pain reduction (with equal pain medication) by at least 2 points on the 5-point pain scale10 or a reduction by at least 1 point if accompanied by a worthwhile decrease (in potency and/or quantity) in pain medication, both for at least 1 month. A minor palliative effect was defined as a decrease of pain and/or pain medication for at least 1 month, but less than the decrease in pain defined as a good palliative effect. No palliative effect meant that there was no decrease in pain or pain medication or that the palliative effect was ⬍ 1 month. The duration of the palliative effect was defined as the period between the start of the combined treatment and the date that pain progression was observed.

Follow-Up During the treatment period and 4 – 6 weeks after treatment was completed, the severity of the pain, the pain medication used, and symptoms of treatmentrelated toxicity were registered weekly. Acute radiation toxicity was scored according to Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer radiation morbidity scores.15 Regular follow-up visits often were not arranged, because patients were treated with palliative intent, and further therapeutic options were not available, except adjustment of pain medication. Follow-up was closed in July, 2001.

Statistical Methods Statistical analysis primarily was descriptive. Primary endpoints for the analysis were occurrence and duration of palliative effect. Patients who showed no pain reduction within 2 months after the start of combined

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treatment were considered failures from the first day of treatment. Patients who showed a palliative effect and had progression of pain during follow-up were considered failures at the date that pain progression was observed. All other patients who showed a palliative effect without pain progression were censored at the date of last contact or date of death. Actuarial methods were applied to calculate the number of patients who had a palliative effect that persisted as a function of time starting from the initiation of treatment. P values ⱕ 0.05 were considered significant. The following factors were analyzed for their correlation with palliative effect and duration of palliative effect: WHO performance status, size of tumor recurrence, and interval between previous radiotherapy and reirradiation.

RESULTS Follow-up ranged from 1 to 36 months (median, 10 months). The median overall survival from the start of combined treatment was 10 months. The overall actuarial 1-year and 2-year survival rates were 43% and 6%, respectively.

Tolerance and Toxicity A total of 198 hyperthermia treatments were given. The temperatures measured within the tumor reached maximum values of 40.2– 44.7 °C, with a median of 41.3 °C. Forty-seven patients (87%) completed the planned combined treatment. Seven patients did not complete the planned hyperthermia treatment. Six of these patients were treated with 28 Gy (1 patient) or 32 Gy (5 patients) and with 3 (instead of 4) hyperthermia treatments. Reasons for canceling 1 hyperthermia treatment were worsening of general condition (n ⫽ 1 patient), patient refusal (n ⫽ 2 patients), interstitial thermometry toxicity (n ⫽ 1 patient), or logistic reasons (n ⫽ 2 patients). One patient was treated with 32 Gy and 4 hyperthermia treatments, but each hyperthermia treatment had to be interrupted because of tumor-induced pain that became unbearable when lying on the treatment couch. No acute treatment-related toxicity was seen in 29 patients. Acute radiation toxicity was a maximum of Grade 2: In 4 patients, limited epidermolysis was observed, and 1 patient developed diarrhea for which medication was given. Three patients had Grade 1 toxicity of the skin, seven patients had Grade 1 toxicity of the bladder, and six patients had Grade 1 toxicity of the bowel. Hyperthermia-related toxicity occurred in 21 patients. A subcutaneous burn—the clinical symptoms of which are a subcutaneous induration, tender for generally not more than a few days, and disappearing spontaneously—was seen in 10 patients. Bacterial

cystitis in relation to the placement of a Foley catheter occurred in two patients. Problems with interstitial thermometry catheters occurred in 9 of 14 patients: A severe infection was seen in 2 patients, a minor subcutaneous infection was seen in 6 patients, and hemorrhage was seen in 1 patient. Toxicity due to interstitial thermometry catheters, as described above, is comparable to the interstitial thermometry toxicity recorded in previous studies in our hospital.14 No signs of severe late toxicity due to combined treatment were observed during follow-up.

Palliative Effect The palliative effect was evaluated in all 54 patients. Complete palliation was achieved in 9 patients (17%), a good palliative effect was achieved in 30 patients (56%), a minor palliative effect was achieved in 6 patients (11%), and no palliative effect or unknown palliative effect was achieved in 9 patients (17%). The median onset of an observed palliative effect was 17 days (range, 1– 60 days) after the start of combined treatment. In the 9 patients who had a complete pain response, no pain recurred in 6 patients during the follow-up period of 1–18 months, and pain progressed in 3 patients after 4 –12 months. The median duration of a good or complete palliative effect was 6 months. Three patients who had a good or complete palliative effect were without pain progression till death, 15 months, 18 months, and 22 months after the initiation of treatment. None of the potentially prognostic factors analyzed were statistically significant for the achievement of a palliative effect, duration of palliation, or overall survival. Figures 1 and 2 show that patients who had a better WHO performance status, a smaller maximum tumor dimension, and a longer time between first radiotherapy and reirradiation all had slightly better outcomes. For patients who had a palliative effect, the fraction of their remaining life without pain progression, on average, was 0.46. For the 30 patients who achieved a good palliative effect, this fraction was 0.42; and, for the 9 patients who achieved a complete palliative effect, this fraction was 0.57.

DISCUSSION This study showed that combined treatment with reirradiation and hyperthermia in patients with unresectable, recurrent colorectal carcinoma is feasible and is tolerated well. The majority of patients completed the planned treatment schedule, and no severe toxicity has been observed. The low morbidity from radiationinduced bowel toxicity may be explained by the limited reirradiation volume. For the majority of patients

Reirradiation and Hyperthermia in Rectal CA/Juffermans et al.

FIGURE 1. Prognostic factors for the palliative effect and for duration of the palliative effect. The percentage of patients who showed a good or complete palliative effect from combined treatment with reirradiation and hyperthermia and progression-free survival according to (A) World Health Organization (WHO) performance status at the initiation of combined treatment, (B) maximum dimension of the recurrent tumor, and (C) interval between previous radiotherapy and reirradiation. N: total number of patients; O: the number of patients without a palliative effect or with pain progression.

who had CT scans available for retrospective analysis, there was little or no small intestine within the radiation volume. Hyperthermia-related toxicity (not taking into account toxicity due to interstitial thermometry catheters) consisted of subcutaneous burns. A subcutaneous burn generally is of minor clinical relevance. Toxicity due to interstitial thermometry catheters was observed in a fairly high percentage of patients (64%;

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FIGURE 2. Prognostic factors for overall survival according to (A) World Health Organization (WHO) performance status at the initiation of combined treatment with reirradiation and hyperthermia, (B) maximum dimension of the recurrent tumor, and (C) the interval between previous radiotherapy and reirradiation. N: total number of patients; O: the number of patients who died.

9 of 14 patients), which, in 1994, led to the decision not to use interstitial thermometry on a routine base. Patients without adequate pain medication also were accepted for combined treatment if they preferred radiotherapy and hyperthermia above adjustment of pain medication. One of the underlying ideas for this acceptance was that, with an increase in pain, combined treatment would become more difficult to complete. A good or complete palliative effect was achieved

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TABLE 3 Published Results on the Palliative Effect in Rectosigmoid Tumors after Radiotherapy with or without Hyperthermia Reference RT without hyperthermia Rao et al.16 Ciatto and Pacini17 Overgaard et al.18 Berdov and Menteshashvili (R)19 Nishimura et al.20 Lybeert et al.21 Guiney et al.22 Knol et al.23 Lingareddy et al.24 van der Zee and Gonza´lez Gonza´les (R)25 Total Radiotherapy with hyperthermia Kakehi et al.26 Berdov and Menteshashvili (R)19 Nishimura et al.20 Gonza´lez Gonza´les et al.27 van der Zee and Gonza´lez Gonza´les (R)25 Current study Total

RT dose (Gy)

No. of patients

Palliative effect (%)

Effect and duration

Various 35–60 23–73 40 Mean, 57 40–44 17–60 34.5 and 54.5 20–41 50–66 —

73 55 75 59 36 95 118 91 52 32 599

84 55 63 32 NR NR 79 75 93 59 68

NR 66% ⬍ 6 mos; 15% ⬎ 1 yr 63% ⬎ 6 mos or until death NR 37% PFS at 6 mos Median, 7 mos PFS NR Median, 2 mos and 4 mos PFS Median, 9 mos Median, 7 mos 2 mos to ⬍ 1 yr

50–60 40 Mean, 58 24–59 50–66 24–32 —

34 56 35 72 40 54 291

56 86 NR 75 68 72 71

NR NR 59% PFS at 6 mos Mean, 12 mos Median, 17 mos Median, 6 mos Median, 6–17 mos

RT: radiation therapy; Gy: grays; NR: not reported; (R): randomized study; PFS: progression-free survival.

in 72% of patients for a mean duration of 6 months. The duration of this effect appears worthwhile, because it lasted for approximately half of the remaining lifetime. The potentially prognostic factors were evaluated to determine whether it would be possible to select patients who have a better chance of benefiting from this combined treatment. Because we found only trends, and the differences in treatment outcomes were not large, we continued to apply the treatment irrespective of these factors. The results of our study do not allow final conclusions on the additional value of hyperthermia in the treatment of patients with recurrent, previously irradiated colorectal carcinoma, because this study did not include a control group of patients who were treated with reirradiation alone. Results published on a palliative effect from radiotherapy either with or without hyperthermia in patients with rectosigmoid tumors are summarized in Table 3. These studies show a wide variety in patient and tumor characteristics, criteria for palliative effect, and radiotherapy dose. Nevertheless, these publications show that, independent of the addition of hyperthermia to radiotherapy, in approximately two-thirds of all patients, a palliative effect was achieved: in 32–93% of patients (total, 68%) after radiation alone and in 56 – 86% of patients (total, 71%) after combined treatment. The results presented in Table 3 suggest that the du-

ration of a palliative effect after combined treatment may be longer than after radiotherapy alone. After combined treatment, the median duration of progression free survival was 6 –17 months, whereas, after radiation alone, the median progression free survival was from 2 months to ⬍ 1 year. In the majority of the studies listed, a conventional fractionation schedule was used with 5 fractions of 1.6 –2.0 Gy per week. Twice weekly, 4 Gy were applied by Berdov and Menteshashvili19 to all patients and by Gonza´lez Gonza´lez et al.27 in a subgroup of 27 patients who were treated with reirradiation. Other than the current study, only three of the listed studies reported on the application of reirradiation. In the studies by Nishimura et al.20 and Gonza´lez Gonza´lez et al.,27 10 of 62 patients and 27 of 72 patients, respectively, were treated with a second course of radiation. The results of the reirradiated patients were not reported separately; only Gonza´lez Gonza´lez et al. reported better palliative effects with higher radiation doses. In the study by Lingareddy et al.,24 all patients were treated with reirradiation. Those investigators used lower fraction sizes (twice-daily 1.2 Gy or once-daily 1.8 or 2.0 Gy) and gave concurrent 5-fluorouracil to 90% of their patients. They observed complete palliation of pain in 65% of their patients. However, the toxicity they observed appears considerably greater compared with what we saw in our study. Concurrent chemotherapy also was applied in

Reirradiation and Hyperthermia in Rectal CA/Juffermans et al.

three other studies. Overgaard et al.18 and Nishimura et al.20 gave concurrent chemotherapy (various drugs) to 9% and 10% of their patients, respectively. Their results from combined therapy were not reported separately. Knol et al.23 combined radiotherapy with 5-fluorouracil in approximately half of their patients. They found no significant differences in overall or symptom-free survival between patients who were treated with or without chemotherapy. Radiation alone was compared to with radiation plus hyperthermia in two randomized studies. Berdov and Menteshashvili19 found a palliative effect in 32% of patients who were treated with radiation alone, compared with 86% of patients who were treated with the combination. van der Zee et al.25 observed a difference mainly in the duration of a palliative effect. After radiation alone, palliation was achieved in 59% of patients for a median of 7 months. After combined treatment, 68% of patients experienced a palliative effect for a median of 17 months. Other approaches to the treatment of patients with local, recurrent rectal carcinoma after previous radiotherapy include, for example, intraarterial chemotherapy and intraoperative radiotherapy. Patt et al.28 reported on the application of intraarterial chemotherapy. They found that intraarterial chemotherapy given into the internal iliac arteries was more effective compared with intravenously applied chemotherapy. A measurable pain decrease was observed in 50% of their patients for a mean of 3.5 months. Intraoperative radiotherapy appears to be worthwhile only in selected situations. The best results were achieved in patients without radiotherapy in their previous history who had tumors that could be resected completely.29,30 The results that we have seen from combined treatment with pelvic reirradiation and hyperthermia indicate that it is worthwhile for the majority of patients with recurrent rectal carcinoma. The additional hyperthermia may prolong the duration of the palliative effect. However, to obtain firm proof of the contribution of hyperthermia to these results, a Phase III study (reirradiation vs. reirradiation and hyperthermia) remains to be performed. In view of the relatively low numbers of patients with the described problem, international cooperation will be required for such a study.

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