Role of radiation therapy in patients with a diagnosis of both systemic lupus erythematosus and cancer

Authors


  • Presented in part at the ASTRO 45th Annual Meeting, Salt Lake City, UT, October 2003.

Abstract

Objective

To determine whether radiation therapy (RT) is denied to patients with lupus and cancer and whether RT causes unusual toxicity in those receiving it.

Methods

We included patients with lupus followed at the University of Toronto Lupus Clinic between 1972 and 2001 who had developed cancer. Demographic, clinical, and laboratory information were collected prospectively. Pathologic proof of cancer was obtained. Three radiation oncologists blinded for the diagnosis of lupus, the modalities of cancer treatment, and the hypothesis of the study reviewed patient data independently. They assessed the indication for RT and whether it should be curative or symptomatic. Recommendation for RT was considered when at least 2 of the 3 radiation oncologists concurred. A review of the literature was conducted.

Results

Forty cases of cancer in 38 patients were identified. Most frequent cancer sites were breast (8), skin (8), digestive (7), and hematologic (7). Median patient age was 58 years. The radiation oncologists recommended RT in 26 cases, either with a curative (14) or a symptomatic intent (12). Only 4 patients received RT, 3 with a curative intent and 1 with a symptomatic intent. None of these 4 patients developed any unusual toxicity. The literature review did not support the fact that lupus patients do not tolerate RT.

Conclusion

Sixty-five percent of our lupus patients with cancer could have received curative or symptomatic RT but only 10% received it. No patient developed any toxicity. RT may be inappropriately withheld from lupus patients with cancer.

INTRODUCTION

Systemic lupus erythematosus (SLE) is the second most common autoimmune disorder after thyroid disease in women of childbearing age, with a female:male ratio of 10:1. The incidence of disease is about 1–2/100,000 persons and the prevalence is ∼40/100,000 persons (1). As SLE patients survive longer, these individuals face a new range of complications from the disease itself and consequences of its treatment.

In particular, an association between SLE and malignancy has been suggested but not yet proven. SLE patients, by virtue of their disease, have basic defects in immune function that could be increased by the immunosuppressive therapy they receive. Several cohort studies showed an increase of non-Hodgkin's lymphoma (2, 3) and of squamous cell skin cancer, especially in patients whose followup was longer than 15 years (4).

Cancer rates worldwide are expected to soar by 20% over the next 20 years (5). The most frequent cancers continue to be breast cancer for women and prostate cancer for men. Lung cancer is the leading cause of death for both men and women, followed by colorectal cancer (6–8). The probability of remission is influenced by the medical interventions given and by the stage of disease at diagnosis.

Radiation therapy (RT) is an essential component of cancer treatment with ∼40% of all cancer patients receiving RT during the course of their disease (9). The goal of RT is to achieve the greatest probability of an uncomplicated cure. In 1992, the American College of Radiology concluded that a “history of collagen vascular disease is a relative contraindication to breast conservation treatment because published reports indicate that such patients tolerate irradiation poorly” (10). This recommendation is based on a few case reports of severe adverse reactions occurring in a few selected patients, most of them with systemic sclerosis (11).

Our goal was to evaluate what has been the role of RT; whether this treatment modality has been avoided as suggested by the American College of Radiology; and whether unusual toxicity was observed in those who did receive RT in a cohort of SLE patients with a diagnosis of cancer.

PATIENTS AND METHODS

The SLE Data Registry at the University of Toronto includes 1,041 cases of patients with SLE that were entered between January 1, 1972 and December 21, 2001. Demographic, clinical, laboratory, and therapy information has been collected prospectively. Among this cohort, 38 patients (3.6%) were identified with a diagnosis of cancer and represent our study population. Details on cancer type, name of the treating oncologist, and treatment delivered were obtained from the registry. Pathology reports were requested from the treating institution. Analysis of the cohort was performed in May 2003 to define their status.

Disease activity was measured by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), a validated measure of disease activity in SLE (12). In addition, disease activity over time was measured by the adjusted mean SLEDAI (13).

Three radiation oncologists, blinded both to the diagnosis of SLE and to the modality of treatment received, independently reviewed patient data, including age, sex, date of diagnosis, cancer site, and pathology report. They determined if there was an indication for RT and the intent of the indication, either symptomatic or curative. Recommendation for RT was defined when at least 2 of the 3 radiation oncologists concurred. The recommendation was then compared with the actual treatment the patient received for cancer. For those who received RT, medical records were reviewed to identify the characteristics of treatment and the complications.

RESULTS

Characteristics of SLE (Table 1).

The majority of patients were menopausal women, with a median age of 55 years. The mean duration of SLE prior to the diagnosis of cancer was 12 years. Only 19% of subjects demonstrated some photosensitivity and 23% were taking immunosuppressive drugs. At the date of cancer diagnosis, a mean SLEDAI-2K of 4.3 and an adjusted mean SLEDAI since diagnosis of 4.6 suggested that these patients exhibited low-to-moderate SLE activity during the followup period.

Table 1. Characteristics of SLE patients at diagnosis of cancer*
CharacteristicsPopulation (n = 38)
  • *

    SLE = systemic lupus erythematosus; SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index 2000; AMS = adjusted mean SLEDAI.

Female:male34:4
Age, years 
 Mean ± SD55.1 ± 17.1
 Median (range)54.9 (21–87)
Menopausal status, yes:no (%)19:14 (57.6)
Smoking habit, yes:no (%)7:24 (22.6)
Photosensitivity, yes:no (%)6:25 (19.4)
Immunosuppressive treatment, yes:no (%)7:24 (22.6)
SLEDAI-2K at SLE presentation 
 Mean ± SD10.2 ± 8.7
 Median (range)6.0 (0–35)
SLEDAI-2K at cancer presentation 
 Mean ± SD4.3 ± 3.9
 Median (range)3.0 (0–12)
AMS 
 Mean ± SD4.66 ± 3.01
 Median (range)4.18 (0–12.2)
SLE duration, years 
 Mean ± SD12.3 ± 10.7
 Median (range)8.1 (0.5–47)

Outcome assessment.

The median survival was 6.2 years (95% confidence interval 3.2–14.1). Twenty patients had died at last followup; 14 deaths were related to the cancer; cause of death was missing in 6 cases.

Characteristics of cancers (Table 2).

Forty cases of cancer were identified, of which 62% were diagnosed in the decade 1990–2000. The most frequent sites were breast, skin, hematologic, and digestive. Eight women developed breast cancer with a median age at diagnosis of 52 years. Four of these women died of breast cancer. There were 8 cases of skin cancers, 5 squamous cell carcinomas, and 3 melanomas. The median age of these patients was 56 years; 2 were dead at last followup. Among the 7 hematologic malignancies, 3 of which were cases of lymphoma, 5 were dead at last followup. Among the 7 digestive cancer cases, 5 colorectal and 2 pancreatic lesions, the median age was 82 years. Six patients in this group died of their cancer. Of the 4 cases of lung cancers, 2 were smokers and 3 were dead at last followup.

Table 2. Characteristics of cancers (n = 40)*
 BreastSkinDigestiveHematologyLungCervixKidneyOvary
  • *

    Two patients had 2 cancers. Values are the median unless indicated otherwise. SLE = systemic lupus erythematosus.

  • Numbers in parentheses for skin, digestive, and hematology malignancies correspond to the following subgroups: skin (squamous cell carcinoma/melanoma); digestive (colorectal/pancreatic); hematologic (lymphoma/leukemia).

Number88 (5/3)7 (5/2)7 (3/4)4411
Age, years5256825858374766
SLE duration at cancer diagnosis, years15685181125
Followup since cancer, years46341864
Number alive45121311
Survival, years6.514161---

Indications for radiation treatment (Table 3).

The 3 radiation oncologists recommended RT in 26 cases (65%), with curative intent in 14 cases and symptomatic intent in 12 cases. The sites where RT with curative intent was recommended were cancers of the breast and skin. The sites where RT with symptomatic intent was recommended were digestive and hematologic malignancies. In reality, only 4 cases (10%) received RT, 3 with curative and 1 with symptomatic intent. None of these patients developed unusual acute or long-term side effects. The cases are described below.

Table 3. Indication for radiation treatment (RT)
SitenRT indicatedIntentRT given
CurativeSymptomatic
  • *

    Two patients had 2 cancers.

Breast87612
Skin86600
Digestive73030
Hematology76151
Lung43120
Cervix41011
Kidney10000
Ovary10000
Total*402614124

Of the 8 cases of breast carcinoma, 6 could have been treated with curative intent and with a conservative approach to treatment. Of these, only 2 had breast conservation surgery (BCS) followed by radiation; 4 underwent complete mastectomy (in the period 1986–1996). None of the cases of skin malignancies, which could have been treated with curative-intent radiation, received it.

Case 1.

A 60-year-old woman was diagnosed with stage IIA cancer of the right breast (T2N0M0) (14). She received 4 cycles of chemotherapy (adriamycin-cyclophosphamide regimen) followed by Tamoxifen. RT regimen consisted of 50 Gray (Gy) in 25 fractions to the entire breast using 6 MV photons followed by a boost (close margin at 1 mm) 10 Gy in 5 fractions using 12 Mev electrons. She developed Grade 2 acute skin reactions (Radiation Therapy Oncology Group scale). No late effects were identified at 12 months followup.

Case 2.

A 54-year-old woman was diagnosed with a stage I cancer of the left breast (T1N0M0) (14). She received 40 Gy in 16 fractions to the entire breast followed by a boost of 12.5 Gy in 5 fractions with a direct electron field. No acute or late side effects at 12 months of followup were documented.

Case 3.

A 27-year-old woman was diagnosed with a stage I low grade lymphoma of the right forehead (14). She received 35 Gy in 20 fractions by an anterior direct field. She developed mild erythema during her treatment but had no long-term side effects after 10 years of followup.

Case 4.

A 67-year-old woman was diagnosed with cervical carcinoma stage IV (14). She received 18 Gy in 10 fractions to the entire pelvis with a box technique followed by 12.5 Gy in 5 fractions with reduced fields with a symptomatic intent. She did not develop any toxicity from her treatment but died of her disease (liver and nodal metastases).

DISCUSSION

This report demonstrates that RT is underutilized in lupus patients with cancer. Of the 40 cases of cancer, 65% could have received radiation, either with curative (54%) or symptomatic (46%) intent, but only 10% of patients received RT.

Among radiation oncologists, the feeling is that patients with connective tissue diseases do not tolerate radiation as well as others. This opinion is based on case reports in the literature. However, in a radiation practice, these cases are not common. In the province of British Columbia, only 5 of the 939 patients (0.5%) with node-negative invasive breast cancer diagnosed in the year 1991 had a diagnosis of SLE or “vasculitis” (15). A review of the recent literature is summarized in Table 4. In summary, adverse events reported include acute and/or late skin reactions in 9 patients; bowel necrosis or obstruction in 3; pneumonitis in 2; and pelvic necrosis, osteomyelitis, osteonecrosis, neuropathy, and encephalopathy in 1 patient each. Two recent studies with SLE patients matched to controls failed to demonstrate an increased radiosensitivity in these patients (16, 17). Four studies reported cases of SLE patients treated by radiation (18–21). Only Fleck et al concluded that SLE patients were more sensitive to radiation: 2 of 3 breast cancer patients with lupus receiving radiation developed acute skin reaction, whereas 1 patient treated with an “unconventional” approach, the “Baclesse technique” developed in France in the 1930s (19), developed late toxicity. Finally, 3 individual case reports discussed acute and late toxicity in SLE and discoid lupus erythematosus patients, questioning the impact of radiation (22–24). Thus, there is no consensus that SLE patients are more radiosensitive than others.

Table 4. Impact of radiation therapy on SLE patients in literature*
Author (ref.)/country/year of publicationDesign/n SLERT complicationsModalities of treatment of case with complicationImpact of RTConclusion
  • *

    SLE = systemic lupus erythematosus; RT = radiation therapy; K = cancer; BCS = breast conservative surgery; Gy = Gray; f = fractions; DLE = discoid lupus erythematosus; CT = chemotherapy; NA = not applicable; CHOP = cyclophosphamide-doxorubicin-vincristine-prednisone regimen; SCLE = subacute cutaneous lupus erythematosus.

Chon and Loeffler (26)/USA/20022:1 matched control/5 SLE + breast KAcute skin: 1 Pneumonitis: 1BCS, 48 Gy in 24f + boost 16 Gy1/5 acute 1/5 lateNo impact
Ross et al (17)/USA/19931:1 matched control/13 SLE + various KBowel necrosis: 140 Gy in 20f pelvis + brachy4/13 acute 1/13 lateNo impact
De Naeyer et al (18)/Belgium/1999Cases: 3 various K (2 SLE, 1 DLE)Acute and late skin: 1 Pneumonitis: 1Mastectomy, 44 Gy in 22f/CT 57.6 Gy in 32f to mediastinum/CT1/3 acute 2/3 lateImpact?
Rakfal and Deutsch (21)/USA/1998Cases: 6 (4 breast; 2 lymphoma) (5 SLE/1 DLE)NoneNA0/6No impact
Morris and Powell (20)/USA/1997Cases: 25 SLE + various KOsteomyelitis: 1 Bowel obstruction: 2 Neuropathy: 1 Encephalopathy: 160 Gy in 34f to mandible 48 Gy in 27f to pelvis 30 Gy in 1f to pelvis 50 Gy in 25f to pelvis 30 Gy in 10f to brain5/25 lateImpact?
Fleck et al (19)/USA/1989Cases: 3 breast K (2 SLE/1 DLE)Acute skin: 1 Acute and late skin: 1 Osteonecrosis: 1Mastectomy/CT/40 Gy, 20f 61 Gy over 10 weeks to breast2/3 acute 1/3 lateImpact
Rathmell and Taylor (23)/UK/1992Case: 1 DLEAcute skin: 1CT (CHOP)/30 Gy in 15f1/1 acuteImpact
Olivotto et al (22)/Canada/1989Case: 1 SLEPelvis necrosis: 140 Gy in 20f pelvis + brachy uterus (38 Gy)1/1 lateImpact?
Urtasun (24)/Canada/1971Case: 1 DLEAcute skin: 161 Gy brachy (Au198)1/1 acuteImpact?
Eedy and Corbett (33)/UK/1988Case: 1 DLEAcute skin: 135 Gy1/1 acuteNo impact
Balabanova et al (34)/Bulgaria/1997Case: 1 SCLEAcute skin: 148 Gy1/1 acute-new onset SCLENo impact

Radiotherapy is associated with a broad spectrum of early and late normal tissue injury. Even within a group of identically treated patients, large variability exists in both the incidence and severity of radiation toxicity, partly the result of the random nature of radiation-induced cell mortality and the variability in intrinsic cellular radiosensitivity among individuals. It is also due to certain cofactors, such as age; hemoglobin level; smoking habits; and the presence of diabetes mellitus, hypertension, or inflammatory bowel disease (25, 26).

Therefore, particularly in women with both a diagnosis of SLE and breast cancer, RT with curative intent could be prescribed more often to those who wish to avoid a complete mastectomy. A recent update of the Health Canada's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer recommended irradiation to the whole breast following BCS for patients with stage I and II breast cancer (27). Postoperative radiation reduces the risk of local recurrence. Prospective, randomized controlled trials have shown that in patients with operable breast cancer, the outcome after BCS followed by radiation was equivalent to that of mastectomy with respect to local and distant recurrence, as well as overall survival (28). Currently, the recommended radiotherapy technique includes treatment of the entire breast with tangential opposed fields using Cobalt 60 beam or X-rays (26). Acute skin reactions during RT of the breast occur in ∼50% of the cases, and may include brisk erythema to confluent moist desquamation (29). The acute skin reactions usually start during the second week of treatment, culminate during the fifth week, and resolve after the tenth week (30). Patients treated with a combination of chemotherapy and radiation therapy are also at higher risk of developing acute skin reaction (31). Furthermore, the acute skin reactions observed at 1 month have been correlated to the long-term cosmetic result of breast radiation (29, 32).

RT with curative intent could also be used for squamous cell carcinoma of the skin as an alternative to surgical resection. Finally, RT with symptomatic intent could be used more often for digestive and hematologic malignancies.

Irradiation to persons with SLE should not be withheld, in particular for women with breast cancer who wish conservative treatment. For discoid lupus erythematosus and SLE with active cutaneous manifestations, caution should perhaps be recommended and the use of standard fractionation, as opposed to accelerated fractionation, could be offered as a safer approach.

Acknowledgements

The authors wish to thank Drs. Charles Hayter, Ewa Szumacher, and Edward Chow for their participation with respect to this work.

Ancillary