CyberKnife® Treatment of Metastatic Malignant Melanoma as Part of a Multimodality Therapy

Metastatic malignant melanoma is an incurable disease with a median survival of 8.5 months and a probability of surviving five years after the diagnosis of less than 5%. To date, no systemic therapy has meaningfully changed these survival end points. A case of metastatic melanoma treated with combined modalities including image-guided robotic radiosurgery with CyberKnife® (Accuray Incorporated, Sunnyvale, CA, USA), and has an overall survival of 14 years is presented.


Introduction
Melanoma is a disease with poor outcomes. Surgical resection is often curative in early, limited-stage disease; however, no effective treatment exists for metastatic melanoma. This is particularly of concern when one considers the increasing incidence of melanoma both in the USA [1] (Fig 1) and worldwide [2]. To date, no treatment has led to any significant prolongation in overall survival (OS) for patients with metastatic melanoma. Herein, we report a case treated with hypofractionated focal radiation delivered by CyberKnife® radiosurgery (SRS), which allows the administration of higher doses with five times less adjacent tissue irradiation compared to 7 to 13 beam-treatments or arc irradiation and far less when compared to conventional fractionated radiotherapy. The higher tumor dose deliverable with SRS should theoretically increase the probability of local control with less late complications.

Radiotherapy
Melanoma is generally believed to be resistant to radiation therapy. However, radiation therapy has been successful in select circumstances: as primary therapy for ocular [3] as adjuvant therapy for post-surgical regional lymph node metastases [4] and finally, as palliation to sites of symptomatic/painful metastases [5]. Recent studies are increasingly advocating the utility of radiation therapy in advanced melanoma. A retrospective study of 84 patients with 114 individually treated tumor lesions showed that higher-dose radiotherapy (>30 Gy) to metastatic lesions not involving the CNS provided significant palliation and prolonged survival [6]. As conventional fractionated radiotherapy can be associated with significant morbidity based on the dose and irradiation site, the limits of its use are constantly undergoing revision. Retrospective reviews of patients treated by higher doses have demonstrated local control. These studies indicate that melanoma is not resistant to higher doses of radiotherapy, and support the use of high doses in a selective manner. CyberKnife radiosurgery (SRS) is particularly useful for the delivery of the higher focal doses required while sparing the nearby organs at risk [7][8] .The technique has been previously described [9].
Briefly, CyberKnife can deliver beams from 1600 or more different directions, a capability that allows it to target lesions precisely. Often 80 to 125 beams of radiation are used in each treatment plan. Using multiple beams of radiation can limit the dose to adjacent structures. The treatment can also be non-Isocentric, which means it does not rely on one point in the tumor and can deliver beams of radiation to any area of the tumor. SRS couples anatomic targeting accuracy and reproducibility with high doses of precise ionizing radiation, thereby maximizing the cell-killing effect on the target(s) while minimizing the probability of radiation-related injury in adjacent normal tissues. Theoretically, when delivered in five fractions versus three fraction schemes there is a higher kill rate; a lower complication rate and the therapeutic ratio is higher. By treating with an ablative dose we then recommend adjunctive chemotherapy.
The system relies on a robotic arm to track gold seed markers (fiducial) implanted in the tumor, which can be tracked through image guidance technology and a real-time respiratory tracking system. A single gold fiducial placed transthoracically under CT guidance into the center of the tumor is visualized with lowenergy (kV) X-rays, fluoroscopy and CT used for geometric verification at the time of dose delivery. (Illustration 1). During the treatment, two orthogonally-placed X-ray units in the room and light emitting diodes (LEDs) placed on the patient's chest are coordinated the respiration, and therefore the target is robotically tracked in real time. Certain especially X-ray-opaque tumors may be tracked without the need for a gold marker. Treatment time can be 1 to 1 1/2 hours. Based on CT and PET/CT imaging, higher doses of radiation appear to improve local control compared to conventional fractionated radiation [10].
Metastasectomy may prolong survival in select circumstances. Should CyberKnife be able to ablate the metastatic lesion without surgery needs further investigation.

Case Presentation
July 1996, a 62-year-old gentleman presented with a bleeding and itching lesion on the posterior aspect of his right shoulder. The family history was non-contributary. The primary lesion was several inches below the collar line on the upper back. Diagnostic biopsy revealed a desmoplastic malignant melanoma of at least Clark's IV. Following an extensive preop work-up that was negative for metastatic disease, a wide excision with axillary sentinal node biopsy was performed. Pathology revealed the lesion to be 5 mm. in depth without node involvement. Antineoplastic therapy was not begun at this time.
Three years later, July 14, 1999, a chest X-ray demonstrated two pulmonary nodules, a 1.6-cm ·mass in the right lower lobe (RLL) and a 0.9-mm mass In the left upper lobe (LUL). July 26, 1999, a fine needle aspiration (FNA) biopsy of the right lung lesion was positive for malignant melanoma. On August 18, 1999, a VATS wedge resection of the RUL nodule was performed followed on September 8, 1999, by the VATS wedge resection of the LUL nodule. Margins of both metastatectomies were reported as free of malignant cells.
The patient subsequently received interferon for one year from September 20, 1999 to October 19, 2000.
A new lesion was found on April 13, 2000, in the RLL, which was detected to be increasing in size.  [11][12]. August 4, 2003: the patient was diagnosed with a right pulmonary artery embolism, which turned out to be secondary to a tumor growing into the right pulmonary artery, and he was started on chemotherapy consisting of Cisplatin, Vinblastine, and DTIC, (six courses from September 2003 to March 2004). The patient responded to the therapy with resolution of the mass.
July 19, 2005: Two new lesions were identified. A parasternal masses of 1.7-cm size and a subcarinal mass of 2.8-cm. It was recommended that he be treated with CyberKnife and chemotherapy. He received 3400 cGy to 100% isodose line and 2550 cGy to the 75% isodose line, to a tumor volume of 6699 mm3, delivered using a 20-mm collimator, 78 non-zero beams, delivered in three fractions. He tolerated the treatment well but did experience a little esophagitis, Grade I, with no other complaints. He completed treatment with higher dose radiosurgery by CyberKnife to the metastasis in the mid-mediastinum on August 12, 2005. He had a complete response to the high dose radiosurgery (SRS course one, mid-mediastinum).
October 2005: a new metastatic melanoma to the subcarinal area of his mediastinum was identified. Again, CyberKnife was indicated. The planned dose was 2400 cGy in three fractions to the 72% isodose line, delivering a 3333.33 cGy to 100% isodose line. A 15-mm collimator was used. Inverse treatment planning was used to deliver the dose covering the planning target volume (PTV), which measured 9 cc. One hundred thirty-four (134) non-zero beams were utilized in three paths. He responded with complete resolution (SRS course two, subcarinal).
PET/CT scans of January 17, 2006, demonstrated interval resolution of lymphadenopathy and FDG activity involving mediastinal lymph nodes that were also present on a prior study of August 5, 2005. No suspicious lesion in this region was found but there were multiple small millimetric lymph nodes in the left supraclavicular and infraclavicular regions with above normal FDG signal that were suspicious for metastatic disease. We followed these metastases in his neck, and they increased in size and become hypermetabolic. April 3, 2007: PET/CT involving a whole body scan indicated stable left supraclavicular nodules unchanged in size since prior study. Although persistent FDG activity was identified, it did appear to have improved compared to the prior study. Postoperative FDG activity probably corresponded to a precarinal lymph node which was likely inflammatory and reactive in nature. No new evidence or other suspicious activity for malignancy or metastatic disease throughout the remainder of the body was encountered.
A PET/CT scan March 24, 2008, when compared to studies of October 29, 2007, demonstrated that the metastatic melanoma in his left neck, supraclavicular area had enlarged from 1.6 cm to 2.3 cm, and had become more hypermetabolic with SUV 9.1.

FIGURE 1:
Pre-CyberKnife CT scan 3/24/2008 demonstration supra-clavicular cluster of left neck lymph nodes metastatic melanoma by fine needle biopsy; fiducial will be placed for synchrony May 1, 2008: He started his third course of high-dose SRS using a 10-mm collimator in three stages giving 3600 cGy to the 70% isodose line covering the lesions which measured 2.234 cc. A total of 124 beams were used by inverse planning and treatment. Maximum dose to the larynx was 639.02 cGy over the course of the treatment. He was treated by fiducial-aided respiratory tracking.   Follow up imaging with CT and PET suggested a complete response of the treated lesions.

Discussion
Resection of metastases is commonly performed for patients whose primary disease is controlled and for whom the metastatic burden is such that all disease can be resected safely. However, some metastasis involves vital structures that prohibit resection. Non-resectional therapies, such as stereotactic body radiation therapy, are being used in centers for patients with oligometastases. Historically radiation therapy has been used in a palliative manor in treatment of metastatic disease. We treat the tumor with ablative intent (curative) and then referrer to medical oncology for adjunctive chemotherapy with curative intent. Because the tumor is never resected with these non-operative interventions, histopathological evaluation of tumor margins for the presence of residual tumor is impossible, and as such, tumor response after each of these therapies is largely based on imaging. The key to successful treatment is early detection of recurrent disease. Therefore, following initial treatment, we obtain PET/CT scans every three months. As soon as a new focus is identified, we initiate treatment. In the past, re-irradiation was limited due to toxicity from wide field radiation, but with modern age guided focal radiotherapy, we can safely re-irradiate and obtain local control.
To date, computerized tomography and computerized tomography-positron emission tomography remain the most readily available modalities for assessment of therapeutic efficacy, and to this end, strict imaging survey and familiarity with the expected imaging characteristics of the treated tumor will aid in recognition of unexpected findings, specifically those of incomplete therapy and/or tumor recurrence. Patients were followed every three months using PET/CT imaging for the first two years, then every four to six months for the remainder of a total of five-year follow-up. Our initial assessment was based on Response Evaluation Criteria in Solid Tumors (RECIST). Any response that was readily assessed using RECIST rules as complete response (CR), partial response (PR), or stable (S) was considered as local control (LC), unless progressive disease (PD) was detected on the subsequent imaging study.
In lung tumor patients treated by high ablative doses, fibrotic or ground glass changes matching the highdose isodose distribution were considered pneumonitis or treatment effects as opposed to disease progression, especially when PET imaging showed no corresponding hypermetabolism. Yet, the frequency of radiographic changes resulting from inflammation and fibrosis in the surrounding parenchyma complicated the local control evaluation. In those cases where the local control was equivocal in this evaluation, we compared the post-images to the planning FDG-PET/CT scans, and compared the overlying treatment dose distribution. This was correlated in nearly all instances by stable or gradually improving characteristic changes in serial studies. If a progressive nodular enlargement, reappearing or enlarging opacities after shrinkage or disappearance, or increasing standardized uptake value (SUV) on FDG-PET within the lesion (PTV) raised suspicions of tumor recurrence, this prompted a pathological exploration.
It has come into focus that associations of adjunctive chemotherapy or targeted therapies and radiation may be used for optimized treatment of limited metastatic disease and that irradiation of the primary tumor may be recommended in the context of metastatic disease. Adjunctive chemotherapy is usually given after surgery where all detectable disease has been removed, but where there remains a statistical risk of relapse due to occult disease, it is recommended following ablative radiosurgery. Adjuvant chemotherapy after resection of Stage II-IIIA non-small-cell lung cancer is now the standard of care based on the results of several international phase III studies using platinum-based regimens.

Conclusions
Metastatic melanoma is increasing in incidence, yet there is no effective therapy for its cure. The most likely success will be in the context of multimodal combination therapeutics. Image-guided robotic radiosurgery with CyberKnife may play an important role in future treatment because of its ability to deliver high doses of radiation with limited toxicity. The treatment should be individualized based upon tumor location, tumor volume, pathology and nuclear grade. Clinical trials will be needed to confirm the findings of this case study.

Additional Information Disclosures
Human subjects: All authors have confirmed that this study did not involve human participants or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.