Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma

To the Editor

The treatment options in renal cancer are few and the response rates are low. It is also a cancer form that has a diverse biology-the vast majority of cases progress rapidly but in a small fraction of patients the progression occurs slowly and in rare cases spontaneous regression are known to occur [1]. These have been reported in virtually all types of human cancer, although the greatest numbers of cases are reported in neuroblastoma, renal cell carcinoma, melanoma and lymphomas/leukemias.

Spontaneous regression of cancer is an interesting phenomenon and elucidating the mechanisms by which it occurs offers the hope that more effective methods of treating and preventing cancer could be developed.

In renal cell carcinomas spontaneous regression predominate in males by a ratio of 3:1. In over 90% of cases, pulmonary metastases are the site of regression. Regression of other sites such as skin, liver, intestine, bone and nodal areas have also been reported [2]. Most frequently spontaneous regression occurs after nephrectomy but the phenomenon has been reported in the absence of surgery or after vascular embolisation, radiofrequency ablation and radiotherapy [1].

Stereotactic radiotherapy (SRT) has been used in our center for almost 15 years for treating inoperable primary tumors of renal cell carcinoma and metastatic lesions in various malignant diseases [3–6]. In 28 renal cell carcinoma patients with treated and untreated metastatic lesions, we have four cases where non-irradiated metastases have regressed temporarily or seemingly permanently after treatment with SRT of either the primary tumor or other metastatic lesions. The frequency of such responses observed in our patient cohort is comparable to the response rates for conventional treatments like interferon and interleukin-2 and is strikingly high compared to the literature, where spontaneous regression of metastasis in renal cell cancer is reported to occur in 0.3–7% of cases [1].

The findings are in agreement with data indicating that local radiation treatment may induce systemic effects, a phenomenon referred to in the literature as the “abscopal effect” [7–12]. The phenomenon has been reported in various tumor forms but mainly as singular events [7], [9], [10], [13], [14].

The term “abscopal effect” caused by radiotherapy was first coined by R. H. Mole in 1953 (abscopal = distant target). This was originally defined as an action at a distance from the irradiated volume but within the same organism [15]. Recently the definition of the abscopal effect has been broadened to include other forms of local therapy that have systemic effects, i.e., a distant bystander effect [16], [17].

The following cases illustrate both the possible induction of an anti-tumoral response against untreated metastases after SRT as well as the efficacy of this therapeutic option in slowly progressing renal cancer where metastatic lesions over time may cause local symptoms.

Case I

An 83-year old female with a history of diabetes type II and a congestive heart failure contacted her physician because of increasing problems with cough. Chest X-ray revealed a large number of metastatic lesions in her lungs (Figure 1). Further investigation with CAT-scan of the abdomen showed a large tumor (6 cm in diameter) in the right kidney. Due to age and poor general condition nephrectomy was not performed and instead it was decided to treat her primary tumor with SRT. At the time of treatment (8 Gy×4 with 3 fractions per week and inhomogenous dose distribution) the metastatic lesions in the lungs were up to 3 cm in diameter and there were enlarged lymph nodes (3 cm in diameter) at the right renal hilum. Follow-up CAT-scans were initially showing stationary lesions in the abdomen but after two years an almost complete regress of the enlarged lymph nodes and a complete regress of the lung lesions were observed (Figure 2). The treated primary tumor remains unchanged in size at 5.5 cm.

Figure 1.  Pulmonary x-ray at diagnoses October 1999 showing multiple lung metastases in both lungs.

Figure 2.  X-ray of lungs February 2005 with complete regression of all metastatic lung lesions.

Case II

A 64-year old female presented with a right-sided abdominal pain and gross hematuria. Medical check-up revealed a right-sided renal tumor, 7 cm in diameter, and she underwent nephrectomy. The pathological exam showed a moderately to poorly differentiated clear and granular cell renal carcinoma (stage 3B). Two months later multiple bilateral pulmonary metastases were diagnosed and interferon + IL-2 treatment was initiated but terminated after one month due to intolerable adverse effects. The patient, who lived abroad, expressed keen interest in obtaining SRT of her metastases in the lungs. In two sessions, two months apart, three respectively five lesions were treated. A CAT-scan five months later revealed a complete or partial regress of the treated metastases and a complete regress of one and a partial regress of five previously seen but not treated metastatic lesions. It was decided to give SRT to the remaining five small metastatic lesions. Six months prior to the last SRT the patient also received treatment with low dose thalidomide (50 mg daily); an agent with documented angiogenesis inhibiting activity at substantially higher doses (200 mg daily). Six months after the last SRT, a CAT-scan showed regress of the treated metastases and no new lesions. Follow-up at four years after last treatment have not revealed any relapse of her disease.

Case III

A 69-year old male previously treated for hypertension was diagnosed with a right-sided kidney tumor and four metastases to the lungs (the largest 2.5 cm in diameter). He underwent nephrectomy and pathological exam revealed renal cell cancer, 10 cm in diameter.

Four months after nephrectomy, the two largest lesions in the lungs were treated with SRT (15 Gy×2). Three months after the radiation therapy, a CAT-scan showed complete regression of the treated and partial regression of the remaining metastatic lesions in the lungs. After another eight months however, a new lesion appeared close to the carina (1.5 cm in diameter). SRT of this lesion and another remaining lesion in the other lung was performed (15 Gy×2). Follow-up after two years has not revealed any relapse of the disease.

Case IV

A 55 year old female suffering from diabetes type II, asthma and previous atrial fibrillation, consulted her doctor because of abdominal pain and macroscopic hematuria. Investigation revealed a 4.5 cm right-sided poorly-differentiated renal cell carcinoma with enlarged local lymph nodes. A surgical attempt to perform nephrectomy was terminated due to the severe adherence of the kidney to the posterior abdominal wall. An extensive lymph node involvement around the kidney hilum (pathologically verified), along the aorta and suspicious lesions on the liver surface was noted during the operation.

After surgery the patient developed a severe depression and declined anti-tumoral treatment. Just over a year after surgery, the patient expressed interest in SRT and it was decided to offer her SRT of the primary tumor despite the extensive lymph node involvement. At the time of treatment the primary tumor was basically unchanged in size as compared to the preoperative CAT-scan. The lymphadenopathy however had progressed in size, with the largest node now measuring 4.5 cm in diameter. The primary tumor was treated with 8 Gy×4 with 3 fractions a week.

After the SRT, the patient developed severe watery, but not blood-contained diarrhea (12 daily) requiring hospitalization. The diarrhea lasted for approximately three months.

Two months after radiation therapy a CAT-scan showed a suspect new lesion in the left lung, 5 mm in diameter but otherwise all other lesions were stationary. Five months after SRT a C¹¹-acetate PET-scan indicated no activity in any of the lesions and at six and nine months after treatment the suspect lesion in the lung is no longer visible and all other lesions are stationary in size.

Discussion

Here we describe four cases of a total of 28 treated patients, who following the SRT exhibited regression of their non-irradiated lesions. These cases are examples of what has been called the abscopal effect of local radiotherapy. The abscopal effect has earlier been classified as a spontaneous regression. The term “spontaneous” was initially used as these effects were generally regarded as inexplicable.

However, spontaneous regression doesn't mean that the effects arise independently of provoking physical- or biological factors. It is now clear that several different mechanisms may be involved, depending on the primary diagnose and provoking factors. Different initiating factors may induce different distant bystander effects. Surgery or radioablation may shift the balance in growth factors or angiogenetic factors produced by the ablated tumor [18–20]. Radiotherapy may evoke other biological responses, including activation of the immune system. Hormonal mechanisms appear to be involved in some instances of spontaneous regression in patients with breast cancer, ovarian, and prostatic carcinomas, malignant melanomas, acute leukemia, hepatocellular carcinoma and sarcomas. Regressions of breast cancer metastases were reported to occur in association with the menopause or with development of ovarian metastases leading to endogenous oophorectomy [21–29]. Other mechanisms with some experimental or clinical support are withdrawal of carcinogens [19], necrosis due to compromise of blood supply by arterial thrombi or caval trombosis [30–33] and epigenetic mechanisms [34].

The mechanisms behind the abscopal effect are poorly understood but there is evidence for two main mechanisms, both of which seem to be dose dependent: the effect may be immune mediated [35] and/or the irradiation may result in the local production of an anti-tumoral or perhaps angiogenesis inhibiting substance [36].

Lately, it has become appreciated that ionizing radiation in higher doses exhibit, besides its direct cytotoxic effects, also various immunomodulatory effects, mainly triggered by inflammatory responses. These are recognized by the innate immune system as “danger signals”, which recruit dendritic cells (DC) to the site. It is known that irradiated tumor cells also serve effectively as a source of tumor antigens. DC acquires these antigens and after maturation migrates to the draining lymph nodes, where they present antigens to T cells. Radiation may thus enhance tumor-specific immunity. Apoptosis in general, spontaneous or caused by low-dose radiation does not induce “danger” and thus does not trigger the immune system.

There are three observations in these case reports that deserve special attention: 1) the relatively high incidence of the abscopal effect in our SRT-treated patients (14%), compared to conventional radiotherapy. This might support the experimental animal studies, where it has been shown that the immunomodulatory effect of radiation is dose dependent with higher doses resulting in better response rates [14], [35]. Furthermore the short time of treatment with SRT might also enhance such immunomodulatory effect as compared to protracted standard-mode radiotherapy, which might pass unrecognized by the immune system; 2) Of the 28 SRT treated patients only four are alive. Three of those responded with abscopal effect. Total survival in the 24 patients without an abscopal response is 25.1 months (2–58) and time to death among the patients in this group who has died was 25.5 months. The survival time for the patients responding with an abscopal effect is 59+ months and time to death for the only patient that has died in this group was 80 months (24–80). This patient died from a heart attack and did not have progressive disease on a follow-up CT a few months prior to her death (Case I). None of the Abscopal patients had favorable disease conditions as they all presented with multiple metastases except for Case II who was diagnosed with multiple lung metastases two months after surgery. Normally such an advanced group of patients would have a dismal prognosis with an expected survival time of less than a year; 3) The majority of responding patients were women (3 of 4). The patient cohort as a whole did not differ from normal incidence of renal cell cancer in the Swedish population (16 males and 11 females). It is well known that women are more prone to some autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, but to our knowledge no gender-related association with prognosis has been reported in immunotherapeutical trials. Interestingly, males predominate in reports of spontaneous regression of renal cell carcinoma.

In the presented cases it cannot be ruled out that factors other than SRT may have initiated the abscopal phenomenon. Case II also received thalidomide treatment, which might have potentiated the process. The dose was however, substantially lower than the doses used in most trials where an anti-tumoral effect of thalidomide has been reported. Cases I and IV differ from the others since the primary tumor and not metastatic lesions were treated. It is known that some tumors produce factors that stimulate the growth of metastatic lesions and these cases may thus be analogous to cases reported with regression of metastatic lesions after nephrectomy.

In conclusion, SRT in renal cancer has been demonstrated as a safe treatment with a high degree of local control (98%) if used correctly. The presented cases indicate that the treatment may also induce a response against untreated metastatic lesions that may result in long-time disease control and survival. The findings argue for a more active and liberal use of SRT in metastatic renal cancer and warrant further studies to define the underlying mechanisms behind such responses as well as studies combining SRT with immunomodulating agents.

This research was supported by Cancerfonden.