Gemcitabine-related radiation recall ... - Wiley Online Library

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Gemcitabine-Related Radiation Recall Preferentially Involves Internal Tissue and Organs Philip A. Friedlander, M.D.1 Roopa Bansal, B.A.2 Lawrence Schwartz, M.D.3 Raquel Wagman, M.D.4 Jerome Posner, M.D.5 Nancy Kemeny, M.D.1

Radiation recall refers to inflammatory reactions triggered by cytotoxic agents and develops in previously irradiated areas. Most reactions develop cutaneously. The most common chemotherapeutic agents implicated are anthracyclines and taxanes. Gemcitabine, a nucleotide analog, recently was implicated in several cases. The authors performed a literature search using PubMed and the search terms “gemcitabine” and “radiation recall” to find prior cases of radiation recall attributed to gemcitabine. These cases were compared with those attributed to anthra-

1

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.

2

cyclines and taxanes. The literature search found 12 cases of radiation recall caused by gemcitabine. The authors also determined that their case of myositis developing

University of Michigan Medical School, Ann Arbor, Michigan.

in the rectus abdominus muscle of a patient with pancreatic adenocarcinoma was

3

Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.

developed radiation recall to gemcitabine and were discussed in the current study

4

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York.

organs or tissues and 30% manifested as a dermatitis or mucositis. This finding

5

the interval from the completion of radiation therapy to the initiation of chemo-

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York.

the manifestation of radiation recall, thereby bringing the number of patients who to 13. Approximately 70% of the cases manifested as inflammation of internal differs from other common agents, in which 63% of the radiation recall events are reported to manifest as a dermatitis. Compared with anthracyclines and taxanes, therapy is less for gemcitabine (median time of 56 days for gemcitabine, compared with 218 days for the taxanes and 646 days for doxorubicin). The majority of radiation recall reactions attributed to gemcitabine are reported to affect internal tissue or organs. In contrast, other common agents for the most part trigger cutaneous inflammation. The development of internal tissue inflammation is reportedly correlated with a shorter interval from the time of completion of radiation therapy to the initiation of chemotherapy. Cancer 2004;100:1793–9. © 2004 American Cancer Society.

KEYWORDS: radiation recall, gemcitabine, carcinoma, pancreatic, interval.

Address for reprints: Nancy Kemeny, M.D., Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; Fax: (212) 794-7186; E-mail: kemenyn@ mskcc.org Dr. Kemeny received grant and research support from Codman, Medtronic, Pharmacia, and Sanofi and is a paid consultant for Codman, Medtronic, and Sanofi. Received February 19, 2004; accepted February 23, 2004.

R

adiation recall refers to inflammation developing in previously irradiated areas that subsequently are exposed to an inciting agent. It is an uncommon event that is observed with a range of cytotoxic agents. In the current study, we present a patient who was treated for locally advanced pancreatic adenocarcinoma and developed a radiation recall myositis when treated with gemcitabine. We reviewed previously reported cases of radiation recall reactions attributed to gemcitabine and found that the vast majority of these reactions manifested as inflammation of internal tissue or organs. This differs from the classic dermatitis reported in the majority of cases of radiation recall attributed to other cytotoxic agents. Potential etiologies for this observed difference with gemcitabine are discussed.

© 2004 American Cancer Society DOI 10.1002/cncr.20229 Published online 2 April 2004 in Wiley InterScience (www.interscience.wiley.com).

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CANCER May 1, 2004 / Volume 100 / Number 9

FIGURE 1. Axial T2-weighted image with fat suppression demonstrating an abnormal increased signal in the subcutaneous tissues of the anterior abdominal wall (arrows).

Case Report A 62-year-old man developed inoperable pancreatic adenocarcinoma, with tumor surrounding the celiac vessels and splenic vein. In October and November 2001, he received three cycles of gemcitabine followed by concomitant gemcitabine and radiation therapy. Radiation therapy was administered to the pancreas and regional lymph nodes (5040 centigrays of 15-millivolt photons in 28 fractions given between October 22 and November 29, 2001 with concurrent biweekly gemcitabine given at a dose of 40 mg/m2). The patient tolerated the treatment well with only WHO Grade 1 nausea and diarrhea reported. Repeat computed tomography demonstrated that the pancreatic mass remained stable. The patient continued to receive weekly gemcitabine at a dose of 1000 mg/m2 for 3 weeks per month with 1 week off. The gemcitabine treatments began 39 days after the completion of radiation therapy. He tolerated the treatment well until approximately 3 months after the end of radiation therapy when he developed severe right upper quadrant abdominal pain associated with movement of the trunk. The pain later spread to the left side of the abdomen, again exacerbated by movement and relieved by rest. It was particularly difficult for the patient to get up from a lying position or to lie down from a sitting position. On examination, the radiation portals, both anterior and posterior, were defined by slight reddening and loss of hair. The rectus muscles were very tender and became painful when stretched.

The patient’s creatine kinase level was 207 U/L (normal values are considered to be ⬍ 120 U/L). Magnetic resonance imaging showed abnormal rim enhancement within the rectus abdominal muscle that was suspicious for myositis (Figs. 1 and 2). The patient was treated with corticosteroids and achieved a complete response. When the steroid dosage was tapered off, the pain did not recur.

LITERATURE REVIEW AND DISCUSSION We performed a literature search using PubMed, with “gemcitabine” and “radiation recall” used as search terms to review prior cases of radiation recall attributed to gemcitabine. We found 12 cases of gemcitabine-related recall reactions in the literature. The characteristics of these cases are summarized in Table 1.1– 8 The reactions were reported to have occurred in patients with a range of primary malignancies including breast carcinoma, nonsmall cell lung carcinoma, pancreatic carcinoma, ovarian carcinoma, and bladder carcinoma. Radiation recall refers to an inflammatory reaction that develops in a previously irradiated area in response to a precipitating agent.9 The reaction often manifests as a dermatitis and can include maculopapular eruptions, vesicle formation, and skin desquamation. Internal organs and muscle are less commonly affected. The reaction tends to occur days to weeks after exposure to the precipitating agent. Recall events

Gemcitabine in Radiation Recall/Friedlander et al.

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FIGURE 2. Axial postcontrast, T1weighted, fat-suppressed images demonstrating abnormal enhancement of the right rectus abdominus muscle (arrows).

have been reported 15 years after radiation treatment but usually occur within months after treatment.10 Although initially reported in 1959 with actinomycin D, radiation recall reactions subsequently have been attributed to a wide range of cytotoxic agents.11 These include taxanes (paclitaxel and docetaxel), anthracyclines (doxorubicin and idarubicin), cytarabine, bleomycin, capecitabine, vinblastine, etoposide, methotrexate, trimetrexate, edatrexate, melphalan, dacarbazine, oxaliplatin, dactinomycin, hydroxyurea, 5-fluorouracil (5-FU), and interferon-␣-2b.4,12–18 Other noncytotoxic agents such as simvastatin, isoniazid, rifampin, pyrazinamide, and tamoxifen also have been implicated.19,20 Despite the wide range of agents implicated, to our knowledge ⬍ 70 cases have been reported since the initial report was published in 1959. In the case presented herein, a patient with pancreatic carcinoma developed radiation recall myositis triggered by gemcitabine. Myositis was demonstrated by clinical observation, symptoms, radiographic imaging, and elevation of the creatine creatine kinase level, and improved with steroid therapy. The inflammation developed 3 months after the completion of the radiation treatments, manifested in the radiation field, and occurred with gemcitabine treatment. This suggests a recall reaction to the radiation triggered by gemcitabine.

Mechanism of Activity and Response to Gemcitabine in Cancer Gemcitabine is an antimetabolite nucleoside analogue that differs from deoxycytidine by two flourines. It is a prodrug that requires phosphorylation by deoxycytidine kinase, a rate-limiting step. This leads to the generation of gemcitabine in the monophosphate, diphosphate, and triphosphate states. Gemcitabine triphosphate incorporates into replicating DNA, leading to cellular apoptosis. The diphosphate form can inhibit ribonucleotide reductase, leading to a decrease in the amount of deoxycytidine triphosphate available to compete for DNA incorporation with the gemcitabine triphosphate. Gemcitabine is cleared through the action of cytidine deaminase and cytidylate deaminase. Gemcitabine has activity against a wide range of common malignancies including lung carcinoma, breast carcinoma, ovarian carcinoma, pancreatic carcinoma, gallbladder carcinoma, and bladder carcinoma. With regard to pancreatic carcinoma, Phase II studies have demonstrated a 10 –15% response rate to gemcitabine and a clinical benefit of 27% as measured by improvements in pain, performance status, and weight loss.21 Clinical benefit can be appreciated in the absence of radiologic response. The radiographic response to gemcitabine can partially be masked by the development of dense desmoplastic reactions.

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TABLE 1 Cases of Radiation Recall with Gemcitabine

Reference

Chemotherapy agent Dose schedule

Bar-Sela et al., 20011

Gemcitabine

1000 mg/m2 weekly

Castellano et al., 20002

Gemcitabine

Burstein, 20003

Gemcitabine, herceptin

Jeter et al., 20024

Gemcitabine, docetaxel

Jeter et al., 20024

Gemcitabine

Jeter et al., 20024

Gemcitabine

1250 mg/m2 on Days 1, 8, and 15 of 28-day cycle 1000 mg/m2 of gemcitabine. Herceptin weekly for 4 weeks 600 mg/m2 of gemcitabine weekly plus docetaxel, 60 mg/m2 every 3 wks for 7 cycles 1000 mg/m2 of gemcitabine, 1 dose 1000 mg/m2 gemcitabine, 1 dose

Jeter et al., 20024

Gemcitabine

Jeter et al., 20024

Gemcitabine

Welsh et al., 19995

Gemcitabine, cisplatin Gemcitabine, cisplatin

Genem et al., 20006

Schwartz et al., 20037 Fogarty et al., 20018

Current study

1000 mg/m2 for 8 weeks gemcitabine every 2 wks 1000 mg/m2 of gemcitabine 1 dose, then 750 mg/m2 weekly for 9 mos Not specified

1000 mg/m2 of gemcitabine weekly on Days 1, 8, and 15 Cisplatin, 100 mg/m2, on Day 15 Gemcitabine 800 mg/m2 every other week Gemcitabine, 1000 mg/m2 of gemcitabine, on Days 1 carboplatin and 8 with carboplatin at AUC ⫽ 5 Day 1 every 3 weeks Gemcitabine 1000 mg/m2 of gemcitabine weekly on Days 1, 8, and 15 of a 28-day cycle

Interval from XRT to chemotherapy

Time until recall reaction

Type of reaction

Tumor type

45 Gy in 25 fractions. 5.4-Gy boost in 3 fractions 24 Gy in 8 fractions

2 mos

6 wks

Dermatitis

NSCLC

4 wks

9 days

Dermatitis

NSCLC

30 Gy in 10 fractions

5.5 mos

2 wks

Dermatitis

Breast


1 wk

7.75 mos

Brainstem radionecrosis

Unknown primary

30 Gy in 10 fractions, 2.5 Gy boost ⫻ 2 30 Gy in 10 fractions to right anterior and posterior chest wall 35 Gy in 14 fractions, 2.5 Gy boost ⫻ 2 50.4 Gy in 28 fractions

3.4 mos

3 days

11 days

10 days

Lower extremity lymphangitis Dermatitis, typhlitis, and colitis

Unknown primary NSCLC

3 mos

3 mos

Optic neuritis

NSCLC

3 wks

9 wks

Pancreatic


4 wks

4 mos

Myositis in rectus muscle, SQ fat stranding Myositis

Bladder


1 mo

3 mos

Myositis

NSCLC


3 mos

15 days

Dermatitis

Ovarian


3 mos

6 wks

Myositis

NSCLC

50.4 Gy in 28 fractions with biweekly gemcitabine

39 days

2 mos

Myositis

Pancreatic

Radiation dose

XRT: radiation therapy; Gy: grays; NSCLC: nonsmall cell lung carcinoma; SQ: subcutaneous; AUC: area under the curve.

A Phase III multicenter trial that compared weekly 5-FU with gemcitabine in the metastatic setting demonstrated a 6% response rate to gemcitabine but a clinical benefit in 24% of the patients studied.22 When treating patients with nonrespectable, locally advanced pancreatic adenocarcinoma, a standard treatment approach is combined chemoradiation followed by chemotherapy. The patient presented in the current study was treated with this approach.

Gemcitabine-Induced Radiation Recall Reactions When evaluating radiation-related reactions, it is important to differentiate radiation recall from radia-

tion sensitization and “impaired healing of an ongoing skin reaction.”9 Radiosensitization refers to the increased effectiveness of radiation due to the activity of sensitizing agents. In animal models, this occurs with agents given up to 3 days after radiation therapy. Reactions occurring within 7 days after the completion of radiation therapy should be classified as sensitization. It has been proposed that for a reaction to be labeled radiation recall any acute radiation-related changes in the skin must be resolved. In 1999, Welsh et al. published what to our knowledge is the first report of a recall event attributed to gemcitabine.5 A patient with metastatic bladder carci-

Gemcitabine in Radiation Recall/Friedlander et al.

noma received radiation therapy (45 grays [Gy] in 18 fractions) to a sacral metastasis. Treatment with gemcitabine and cisplatin was initiated 4 weeks after the radiation therapy was completed. Clinically apparent myositis developed in the gluteal muscle after three cycles of chemotherapy. The treatment was withheld and the myositis resolved with prednisone therapy. Ganem et al.6 published a similar report of a patient who received radiation (33 Gy in 11 fractions) using anterior and posterior fields to a bone metastasis in the right puboischiatic region. Treatment with gemcitabine and cisplatin was initiated 1 month after radiation therapy and dermatomyositis was reported to have developed in the gluteal muscle after 3 cycles. Classic radiation recall often occurs with the initiation of the precipitating agent but can occur after several courses of treatment. Radiation recall reactions traditionally have been reported to manifest as a dermatitis. Burstein published what to our knowledge is the first reported case of a recall dermatitis attributed to gemcitabine in a patient with advanced breast carcinoma who received radiation therapy (30 Gy in 10 fractions) to a metastasis in the lumbosacral vertebrae.3 Treatment with gemcitabine was initiated 5 months after the completion of radiation therapy. After two treatments, a dermatitis confined to the irradiated region developed. The dermatitis improved when gemcitabine therapy was withdrawn. It is interesting to note that no reaction developed at the site of the breast and chest wall irradiation that was received 3 years previously. In the current study, we presented a case of a patient being treated for locally advanced pancreatic adenocarcinoma who developed myositis that was attributed to a gemcitabine-induced radiation recall reaction. Both this patient and the patient presented in the study by Jeter et al.4 developed myositis in the rectus abdominus muscles while being treated with gemcitabine after the completion of chemoradiation to the pancreatic bed. Both patients received the same dose of radiation (50.4 Gy in 28 fractions), but the choice of radiosensitizer differed. Our patient received gemcitabine as a radiosensitizer whereas the other patient received infusional 5-FU. As such, it is highly unlikely that the myositis noted in our case was conditional on the use of gemcitabine for radiosensitization. Neither patient developed the myositis after the initial doses of postradiation gemcitabine were given but rather after 2 months of treatment.

Manifestations of Radiation Recall Reactions Attributed to Gemcitabine Differ from Other Agents In their review of radiation recall dermatitis, Camidge and Price reported that the interval between ra-

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diation therapy and chemotherapy leading to the reaction ranges from days to years.9 The reaction typically develops hours to days after the administration of the instigating agent but could occur after weeks of treatment. With regard to myositis, skeletal muscle is relatively resistant to injury from radiation. A retrospective analysis demonstrated that increasing the total dose and the dose per fraction of radiation but not the length of the treatment increased the likelihood of developing muscle injury.23 In a recent review of radiation recall, the vast majority of cases were attributed to anthracyclines and taxanes (69%). Radiation recall reactions most often developed in the skin but occasionally were noted in the muscle, lungs, bowel, esophagus, central nervous system, and vulva. Approximately 63% of the total radiation recall events manifested as a dermatitis. The time interval from the completion of radiation therapy to the development of radiation recall phenomena reportedly varies from weeks to years. There are cases of radiation recall dermatitis reported to have developed as soon as 8 days and as long as 15 years after radiation therapy. This finding differs from that noted with gemcitabine in the current study in which only 4 of the 13 reported cases (31%) manifested as a dermatitis or mucositis. Approximately 70% of the cases involved inflammation in internal tissue or organs. Therefore, although the majority of radiation recall cases involving the two most common inciting agents (i.e., taxanes and doxorubicin) manifest as a dermatitis or mucositis, the vast majority of reported cases involving gemcitabine occur in the internal tissue/organs. To our knowledge, the reason for this observed difference is not clear. It may be related to the underlying etiology of radiation recall reactions, which essentially is not known. Several possible causes have been proposed. These include radiation-induced alterations of the pharmacodynamics of the chemotherapeutic agent,19 changes in epithelial stem cells,24 –27 and idiosyncratic drug hypersensitivity reactions.9,28 Radiation induces injury to exposed cells, most likely with changes to the intracellular expression and activity of various proteins. Radiation exposure also possibly may alter the expression or activity of deoxycytidine kinase or cytidine deaminase in a subset of patients, leading to the altered pharmacodynamics of gemcitabine facilitating a radiation recall event. As such, perhaps a relatively short interval between the completion of radiation therapy and the initiation of chemotherapy would facilitate the development of inflammatory changes. We examined the time interval from the comple-

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TABLE 2 Recall Reactions as a Function of Time from Completion of Radiation Therapy to the Initiation of Chemotherapy

Chemotherapy agent

No. of cases

Average time from XRT to chemotherapy, in daysa

Gemcitabine Paclitaxel or docetaxelb Doxorubicinb

13 9 11

58 218 646

% involving internal tissue or organs

% limited to dermatitis and mucositis

Average time from XRT to chemotherapy (patients with dermatitis/ mucositis only), in daysc

Average time from XRT to chemotherapy (internal tissue involvement), in daysa

70% 12% 45%

30% 88% 55%

85 241 968

46 12 246

XRT: radiation therapy. a Days estimated assuming a reported month equals 30 days. b Based on patients reported in, Jeter M, Pasi J, Brooks S, et al. Gemcitabine-induced radiation recall. Int J Radiat Oncol Biol Phys. 2002;53:394–400.

tion of radiation therapy to the initiation of chemotherapy in those patients with radiation recall due to gemcitabine and compared this time interval with that of the patients reviewed in the study by Jeter et al.4 who developed radiation recall as a result of treatment with the taxanes or doxorubicin (Table 2). We found a much shorter time interval with the use of gemcitabine. The average time from the completion of radiation therapy to the initiation of taxane treatment was reported to be 218 days. For doxorubicin, the average time was 646 days. Conversely, the average time for gemcitabine was only 56 days. Furthermore, for each individual agent, the time interval from the completion of radiation therapy to the initiation of chemotherapy was found to be less in the subset of patients who developed tissue or organ inflammation (46 days vs. 85 days for gemcitabine, 12 days vs. 241 days for the taxanes, and 246 days vs. 968 days for doxorubicin). Therefore, even for the taxanes and doxorubicin, a shorter interval appears to be correlated with internal inflammation. Gemcitabine is a commonly used chemotherapeutic agent and when monitoring patients receiving treatment with this agent, one should remember the possibility of radiation recall reactions. Furthermore, a review of the literature suggests that radiation recall reactions due to gemcitabine affect internal tissue/ organs disproportionately to that noted with other common agents. This may be the result of a briefer interval between the completion of radiation therapy and the initiation of gemcitabine therapy. Additional reports of radiation recall reactions observed with gemcitabine should help to clarify this interesting observation.

2.

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