CyberKnife for Recurrent Disease

Several hundred thousand patients receive each year in the United States for a large variety of malignancies. The most commonly treated body sites include the lung, breast, prostate, pelvis, abdomen, central chest (mediastinum), head/neck, bones (usually for metastases – tumor deposits that have spread to the bone from other malignant primary tumors), lymph nodes, gynecologic organs and brain. Although radiotherapy technology continues to improve, resulting in ever improving cure rates, there is a measurable relapse rate for every treated site in the human body, ranging all the way from <10% (e.g. – stage I Prostate Cancer, stage I Breast Cancer) to virtually 100% (e.g. – Glioblastoma Multiforme – a highly malignant brain tumor).

Feasibility of further Radiotherapy

In addition to treating the tumor volume, some amount of normal body tissue is also treated with every course of radiotherapy, particularly tissue that resides in close proximity to the tumor volume (12). As each tissue in the human body has a finite radiation tolerance, if the initial radiotherapy course fails to control the tumor, it is often not safe to give additional meaningful radiotherapy, without taking undue risk of damaging the target region normal tissue. Radiation induced local tissue damage may result in an injury that is as or more severe than the local effect of the tumor itself.

Because the retreatment dose is usually limited, radiation retreatment using conventional techniques is usually palliative. Palliative radiation is given to control symptoms but is not likely to cure the treated lesion (1234567891011). Higher dose potentially curative re-irradiation has been applied in recurrent head/neck, gynecologic, prostate and breast cancers (12131415161718192021).  One feature seen in re-irradiation for cure as opposed to palliation appears to be the feasibility of brachytherapy as part or all of the retreatment regimen, suggesting that the application of a more concentrated, high dose of radiation will be more likely to produce long-term disease-free survival or cure where “conventional” radiation has failed (131415). In other curative intent retreatment cases, the limited tolerance to additional external beam irradiation is augmented by conservative surgery (12), or the addition of chemotherapy to the regimen, usually delivered concurrently, with occasional long-term survivors reported (161718192021).

When reirradiation +/- chemotherapy is done for cure, the complication list may be formidable, as illustrated by the head/neck retreatment series reported by DeCrevoisier, et al, describing an elevated incidence of severe soft tissue fibrosis, bone and soft tissue necrosis, and fatal carotid hemorrhage (16). Other investigators have also reported formidable head and neck cancer retreatment complications ( 17,1821). Intensity modulated radiotherapy (IMRT) + chemotherapy salvage treatment may have a more favorable retreatment benefit to risk ratio for head and neck cancer relapse patients, presumably reflecting the more favorable dose sculpting characteristics of  IMRT, leading to better sparing of normal tissues compared with conventional techniques ( 19). In the case of salvage brachytherapy as potentially curative treatment of post-radiation recurrent prostate cancer, the risk of incontinence compared de novo brachytherapy is substantially higher, at 24%, again illustrating the hazard of applying even localized additional high dose radiation therapy after primary radiotherapy relapse (14).

In summary, the scope of radiation relapse situations is varied, and their management challenging.  Due to limited normal tissue tolerance to additional radiation, conventional radiation retreatment is usually palliative, unless an intensification measure such as brachytherapy, chemotherapy or surgery is also possible. When reirradiation is done with curative intent, the risk of complications may be  significantly increased compared with de novo radiotherapy. Due to the wide variety of unique relapse scenarios, published medical literature often provides little guidance in these cases.

Feasibility of surgical removal

Surgical resection is another consideration for localized persistence of a tumor following radiotherapy. In some cases, this is a viable option, whereas other patients will not be eligible for surgical salvage, due to issues such as poor overall  health, damaged tissue in the irradiated field increasing the surgical complication risk, or due to the presence of a widely infiltrating relapse lesion that is unlikely to be completely removed.

Due to the technical problems and seriousness of potential complications, surgical resection is more commonly performed in a post-radiation relapsed lesion that is still potentially curable, such as persisting prostate, bladder, esophageal, or head and neck cancer following radiotherapy (22-30). This is in distinct contrast to re-irradiation, which is often less radical in its intent and more commonly applied for palliation (symptom control).

If resective surgery is undertaken for a radiotherapy relapse situation, the operation will typically be more difficult than a similar operation performed in the absence of prior radiotherapy (25), the effectiveness may be lower (23,29,30), and the complication rate likely increased (24,25,27,28), including fatal complications (27,28).

Stereotactic Radiosurgery

A new paradigm for post-radiotherapy relapse

There is accumulating evidence that stereotactic radiosurgery is a very effective option for patients with lesions that have relapsed after traditional radiotherapy, avoiding some of the problems associated with traditional radiotherapy or surgery (31-47).

Compared with conventional radiotherapy, radiosurgery creates a far more precise dose distribution and highly conformal therapeutic margin, much more effectively limiting the normal tissue exposure to excessive radiation. This allows a more biologically potent radiation application, creating a greater possibility for durable local control and long-term disease-free survival, compared with re-irradiation using conventional techniques. This allows a more biologically potent radiation application, creating a greater possibility for durable local control and long-term disease-free survival, compared with  re-irradiation using conventional techniques.

Site specific stereotactic radiosurgery/radiotherapy retreatment

Head and Neck/Skull base cancers

There is considerable evidence that radiosurgical salvage of post-radiotherapy skull base and nasopharynx relapses provides durable local control in a high percentage of patients, with an apparently lower complication rate than is seen with conventional reirradiation techniques (31-36). The preponderance of published radiosurgery experience for recurrent head and neck lesions has been gained with Gamma Knife radiosurgery.

The frameless CyberKnife® design, multiple treatment capability, and virtually unlimited dose-coverage capability compared with Gamma Knife indicates a much larger spectrum of applicability to recurrent head and neck lesions with CyberKnife®.

Case Studies:

Left Optic Nerve Meningioma (WHO Grade 2)
Barrow Neurological Institute
Meningioma (Optic Chiasm)
Stanford University Medical Center

Recurrent lung cancer

Symptomatic recurrence of lung cancer after radiotherapy has been successfully retreated with stereotactic radiotherapy, producing high rates of symptomatic relief with minimal complications (37,38), though large doses delivered to the central chest are capable of producing severe or even fatal complications (37), mandating caution when treating central (mediastinal) recurrent lesions. It should be noted that CyberKnife® radiosurgery with Synchrony respiratory tracking creates a more focal high dose region with a sharper margin than that created by the techniques described in these references, further reducing normal tissue complication risk with CyberKnife®.

Recurrent Central Nervous System (CNS) lesions

Primary CNS tumor recurrences after radiotherapy (38,39) and recurrent brain metastases (40) have been safely retreated with radiosurgery (38,40) or stereotactic radiotherapy (39).

Recurrent primary CNS tumors have been radiosurgically treated with survival extension of 7-8 months and no significant complications (38,39). Occasional long-term survivals in patients with small volume recurrences have been reported (38,39).

The retreatment result has been more durable with radiosurgery for recurrent brain metastases (metastases means tumors that have spread to the brain from primary malignant tumors elsewhere in the body), with an 84% rate of local control 2 years following radiosurgical retreatment (40). In the case of brain metastatic lesions, the 84% 2 year local control rate and 57% overall brain disease-free rate appears to significantly exceed the result reported with standard radiotherapy retreatment (11).

Recurrent Spine Lesions

A significant body of literature has been developed describing the effectiveness of a variety of sophisticated radiotherapy and radiosurgery approaches for vertebral (spine) metastases that have recurred after conventional radiotherapy (41,42,43,43,44,45,46). It is particularly noteworthy that recurrent renal cell carcinoma (RCC) and melanoma spine metastases, traditionally considered “radioresistant,” have demonstrated a response rate on the order of 90% to retreatment with CyberKnife® radiosurgery, with an absence of serious neurologic complications (43,44).

Single or multiple CyberKnife® radiosurgical approaches to maximize tumor control and minimize the risk of spinal cord radiation injury have been developed, with one center the number of treatments according to an 11 point spinal cord injury risk scoring system (46). This regimen has produced durable pain relief and no neurologic complications, in a series of 107 patients, all of whom had relapsed after prior conventional spinal radiation therapy (46).

Though spinal retreatment has also been accomplished with conventional radiation (1,2,3), the response rate and durability of response appears lower compared with the radiosurgical results (43,44,45,46).

Radiation myelopathy (spinal cord injury that may result in paralysis) has also been observed in occasional patients following spinal retreatment with conventional radiotherapy technique (1,2,3), which has not been reported in the radiosurgical series (43-46).

Recurrent pelvic tumors

A newly emerging CyberKnife® radiosurgery application is the retreatment of pelvic tumors, including gynecologic, prostate and colorectal cancers that have recurred after prior external beam radiotherapy (47). Traditionally, due to the close approximation of these tumor masses to sensitive pelvic tissues, including colon, rectum, bladder and small intestine, these patients have had little additional local treatment option available to them. The preliminary CyberKnife® radiosurgery response rate for these recurrent pelvic lesions is an encouraging 80%, with minimal toxicity, as long as centrally recurrent lesions with intimate bowel loop association are avoided (47).

Case Study:

Recurrent Rectal Cancer
Erasmus Medical Center - Rotterdam

Conclusion

The tumor ablative potential of radiosurgery is more biologically potent compared with conventional radiotherapy, and thus, more likely to provide a durable retreatment success after conventional radiotherapy has failed. Because the radiosurgery dose volume is tightly conforming to the retreatment target volume, the potential for serious radiation induced tissue complications is reduced. Compared with traditional surgery for radiotherapy failure, radiosurgical treatment avoids a large operation, and thus avoids the potential wound healing problems and other complications associated with operating on tissues that have been devitalized by prior radiation therapy.

Due to its unique dose sculpting and tumor tracking capability, including Synchrony respiratory tracking, CyberKnife® radiosurgery spares more normal tissue from high dose reirradiation than any other radiosurgery system, over a much wider variety of body sites, making this device an ideal choice for retreatment of post-radiotherapy relapse lesions.

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