Durable control of locally recurrent renal cell carcinoma using stereotactic body radiotherapy

Abstract

Renal cell carcinoma (RCC) is generally poorly responsive to conventional radiation doses, and patients with inoperable local recurrence have limited therapeutic options. Stereotactic body radiotherapy (SBRT) is an increasingly available technology that allows delivery of a radiation schedule providing doses far more biologically effective against cancer cells than conventional radiotherapy. We present a case where durable disease control was achieved using SBRT in a patient with inoperable locally recurrent RCC who presented 18 years from original nephrectomy. The patient remains asymptomatic with no evidence of active disease 30 months following SBRT. This case highlights the need to reconsider the role of therapies with continuing advances in technology.

Background

Radiation therapy has been minimally effective for renal cell carcinoma (RCC) at traditional dosing schedules. However, stereotactic body radiotherapy (SBRT) is an increasingly available technology that differs from conventional radiotherapy in that it can safely deliver much larger doses of radiation per fraction. Indeed, SBRT can provide local control with acceptable toxicity for inoperable RCC.^{1 2} We present the first case reporting durable control following SBRT for an inoperable local recurrence of RCC and describe vertebral bone changes following SBRT that may be mistaken for tumour. This report also serves to highlight the importance of a multidisciplinary team to optimise the management of challenging patients and foster the consideration of new therapeutic options.

Case presentation

A 72-year-old man with a 4-month history of progressive back pain, anorexia and weight loss presented 18 years following radical nephrectomy for RCC. The pain had rapidly increased in intensity over a 2-week period requiring hospital admission through the emergency department and opioid analgaesia. The patient had no comorbid disease and no other signs or symptoms.

Investigations

CT of the abdomen revealed a solid mass involving the inferior vena cava (IVC) and right psoas muscle. MRI confirmed a 5.2×3.0×4.6 cm mass encasing the IVC and invading the anterolateral L2 vertebral body (figure 1A). No other disease was evident on chest CT or full body bone scan.

Figure 1.

(A) Abdominal MRI axial T2, fat suppressed T1 and coronal bright blood images (left to right) performed pre stereotactic body radiotherapy (SBRT), (B) 4 months post-SBRT and (C) 8 months post-SBRT demonstrating the locally recurrent renal cell carcinoma in the right psoas muscle. After SBRT, a mass remains but has decreased in size and has become internally haemorrhagic and necrotic (increased T1 signal in B and C). Typical postradiotherapy changes are also noticed in the spine with complete fatty replacement of the marrow.

Differential diagnosis

The location and invasive appearance of the mass indicated local RCC recurrence from the resection bed soft tissue or hilar lymph nodes. Biopsy was performed to confirm the diagnosis due to the long latency period since original diagnosis. CT-guided core biopsy confirmed a well-differentiated adenocarcinoma negative for CK7 and CK20 with coexpression of vimentin consistent with RCC.

Treatment

The clinical case was discussed by a multidisciplinary team involving surgeons (urologic oncology, vascular and orthopaedic oncology), oncologists (radiation and medical), radiologists and pathologists. It was believed that surgical resection would require IVC replacement and significant vertebral/nerve root resection resulting in certain risk of treatment morbidity. Systemic-targeted therapy was also considered as a palliative option. However, in view of the isolated site of disease, it was felt that localised treatment was preferable and SBRT was offered to the patient.

The patient underwent a treatment planning CT simulation scan (1 mm axial cuts) and pregadolinium and postgadolinium contrast MRI. The MRI and CT were coregistered in the Cyberknife Treatment Planning System. The tumour and normal critical structures were contoured by the Radiation Oncologist. A customised SBRT plan using 148 beams (figure 2) was developed to deliver a maximum tumour dose of 50 Gy in three fractions with a tumour margin dose of 39 Gy in three fractions (78% isodose), while keeping the dose to surrounding organs (the duodenum, bowel, spinal cord and left kidney) within accepted tolerance limits.³ This treatment dose prescription offered a high probability of local tumour control based on outcomes from SBRT protocols for inoperable primary renal tumours.¹ The patient was treated with SBRT on the Cyberknife system (Accuray Inc) using spine tracking for accurate treatment delivery. Fiducial markers were not required as the recurrent tumour was fixed to bone.

Figure 2.

Axial slice of the patient's stereotactic body radiotherapy treatment plan showing radiation dose distribution. The shaded red region is the target; the other lines represent radiation isodoses. The majority of the target is covered by the 44 Gy isodose (88%) with the 39 Gy isodose (78%) covering the target margins except for one small anterior region immediately abutting small bowel. Although the dose fall-off outside the target is rapid, a large proportion of the vertebral body still receives a considerable dose of radiation.

Outcome and follow-up

Within 24 h of the first fraction of SBRT, the patient experienced an initial pain flare requiring an increase in analgaesia. However, the pain had completely resolved in 1 week following treatment allowing discontinuation of all analgaesics. He returned to regular physical activity, including golf, within 6 weeks. He had no other acute toxicities related to the SBRT. MRI of the abdomen 4 months post-treatment showed a slight reduction in the dimensions of the mass, but a significant change in signal characteristics with central tumour necrosis indicating treatment response (figure 1B). His case was rediscussed at the multidisciplinary tumour board and a surveillance approach with 4 monthly MRIs was planned.

MRI 8 months post-SBRT showed a reduction in the dimensions of the mass to 5.0×1.8×3.7 cm, with resolution of the contiguous vertebral body invasion (figure 1C); however, there was suspicion of progressive disease in the L2 vertebral body adjacent to the treated region. The differential diagnosis was cancer recurrence or radiotherapy-related benign vertebral changes. Clinically, the patient remained asymptomatic and active. No biopsy was performed and the multidisciplinary team recommended continued surveillance of the patient.

Within 12 months post-treatment, the MRI changes were more consistent with radiotherapy changes than with disease progression. There was fatty marrow replacement within the L1–L3 vertebrae with a subacute radiation-induced fracture of L2 without the loss of vertebral body height. The paravertebral soft tissue mass was stable and the residual was felt likely to represent inactive necrotic/fibrotic tissue. At this time, the patient had minimal back pain requiring non-opioid analgaesia and no neurological symptoms or signs. Figure 3A–E depicts the evolution of the spinal insufficiency fracture. Imaging frequency was extended to every 6 months after 2 years. Thirty months postradiation, the patient remains well and pain free. The size of the tumour mass on MRI remains unchanged from 8 months post-treatment. Systemic restaging CT and bone scan showed no evidence of distant disease.

Figure 3.

Sagittal T1-weighted MRIs performed post-stereotactic body radiotherapy demonstrating the evolution of an insufficiency fracture in the L2 vertebral body at (A) 8 months, (B) 12 months, (C) 20 months and (D) 28 months, with (E) sagittal CT image from 28 months. Note progressive involvement of the vertebral body over time but lack of an associated soft tissue mass and relative preservation of osseous components of the fracture (best seen on CT), features that are in keeping with insufficiency fracture rather than pathological fracture from metastatic disease.

Discussion

Local recurrence of RCC following nephrectomy without concomitant metastatic disease is relatively rare, occurring in approximately 2% of patients.^{4 5} These patients may be cured or experience long-term disease-free periods from local salvage treatment. Complete surgical resection of the local recurrence with clear margins is associated with improved survival.^{4 5} However, surgery may be associated with significant morbidity due to tumour invasion of surrounding critical structures or due to patient comorbidities. Traditional treatment of surgically unresectable local recurrence is palliative surveillance and systemic therapy. Conventional radiotherapy to palliate symptoms may have been offered to severely symptomatic patients, but radiation doses were limited because of toxicity to normal tissues. This is the first report to our knowledge of treatment of a locally recurrent RCC with SBRT and indicates that SBRT is likely to be a valid treatment option for inoperable cases with the potential for durable disease control.

SBRT uses a linear accelerator to deliver the same high-energy ionising photon beams as conventional radiotherapy. The fundamental difference between these radiation modalities is that SBRT uses many more radiation beams, which results in a sharp dose gradient outside the target. Furthermore, target volumes with SBRT are minimised because better patient immobilisation and image guidance during treatment delivery reduce the additional margin required to account for set-up error and tumour movement during treatment. As a result, far higher radiation doses per fraction can be delivered to the tumour without exceeding the tolerance levels of the surrounding normal tissue. Increasing the radiation dose per fraction increases the biological effect of radiation on tissue and results in higher tumour control probability.^6–8

However, as demonstrated in figure 2, while the dose fall-off outside of the target is rapid with SBRT, tissue immediately adjacent to the target still receives high doses. As SBRT is a relatively new field, normal tissue tolerances are less certain compared with conventional radiotherapy. In this case, the patient experienced a vertebral compression fracture following SBRT. Although this is a recognised potential complication of spinal SBRT, the fact that the patient had partial vertebral body erosion from the tumour prior to treatment probably increased the chances of subsequent fracture as lytic tumour is a significant risk factor for spinal fracture following SBRT.⁹ Symptoms from SBRT-related vertebral compression fracture often settle with conservative management, but vertebroplasty or surgery may be required.⁹

The traditional paradigm of RCCs as radioresistant derives from laboratory studies showing a high surviving fraction of RCC cells in culture following 2 Gy of radiation¹⁰ and a lack of survival benefit reported in the 1970s and 1980s with perioperative conventionally fractionated radiotherapy.^{11 12} However, clonogenic survival assays indicate that RCC is radiosensitive to high doses per fraction.¹⁰ This principle is supported by many accounts of successful symptom improvement and tumour response/control rates following the use of large fraction sizes using stereotactic radiation for RCC metastases, particularly in the brain and spine.^13–15 A recent review of SBRT for inoperable primary RCC reported weighted local control rates of 94% with a weighted severe adverse event rate of 3.8%.¹ Whether patients who undergo surgery for local recurrence could benefit from preoperative or postoperative SBRT warrants consideration.

This case also illustrates the benefits of discussing challenging cases within a multidisciplinary team in view of continued advances in surgical techniques, drug development and radiotherapy technology. Multidisciplinary case discussion allows all potential management options, including new developments, to be fairly considered and an appropriate plan developed for the individual patient. Such an approach also fosters the consideration of a differential diagnosis. The long latency period between this patient's primary RCC and recurrent disease necessitated tissue confirmation as a second primary, metastatic tumour or even a non-malignant condition were possibilities. Furthermore, the MRI 8-month post-SBRT was reported as highly concerning for disease progression. However, following multidisciplinary team review, post-therapy changes were deemed more probable and a surveillance approach was adopted. Whether imaging abnormalities after radiotherapy represent progressive disease or merely reflect treatment is a dilemma increasingly faced in oncology. Erroneously diagnosing disease progression has major implications. Advanced imaging modalities, such as diffusion/perfusion MRI or positron-emission tomography scans, can sometimes be helpful in distinguishing tumour from postradiation effects, but are rarely definitive. In some circumstances biopsy may be warranted, but in the context of the appropriate clinical picture, interval reimaging following a period of observation is often the best approach and allows the true cause of post-treatment imaging changes to become apparent. Clinicians and patients can find the uncertainty during a period of observation challenging and the endorsement of the multidisciplinary team validates such an approach.

In summary, we have described how SBRT can achieve durable control of a locally recurrent RCC, a tumour type traditionally thought to be radioresistant. This emphasises the need to re-evaluate the role of therapies with advances in technology and underlines the benefit of multidisciplinary collaboration in challenging cases.

Learning points.

• Stereotactic body radiotherapy can deliver doses of radiation to tumours with a greater biological effect than conventional radiotherapy, with acceptable morbidity.

• Stereotactic body radiotherapy is a treatment option that can offer durable local control in locally recurrent inoperable renal cell carcinoma.

• The rapid evolution of radiation technology requires us to reconsider its role in tumour types previously thought to be radioresistant. Similar principles apply with advances in surgical techniques and drug development.

• Discussion of challenging cases within a multidisciplinary team is valuable to individualise management plans taking into account up-to-date opinions from specialists in various fields.

• The potential for imaging abnormalities to reflect postradiotherapy changes should be considered before diagnosing progressive disease in patients with cancer.