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 (1, 2). 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 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11). Higher dose potentially curative re-irradiation has been applied in recurrent head/neck, gynecologic, prostate and breast cancers (12, 13, 14, 15, 16, 17, 18, 19, 20, 21). 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 (13, 14, 15). 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 (16, 17, 18, 19, 20, 21).
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 ( 17,18, 21). 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 Rectal Cancer
- Erasmus Medical Center - Rotterdam
- Rades D, Stalpers LJ, Veninga T, Hoskin PJ. Spinal reirradiation after short-course RT for metastatic spinal cord compression. Int J Radiat Oncol Biol Phys. 2005 Nov 1;63(3):872-5
- Wong CS, Van Dyk J, Milosevic M, Laperriere NJ. Radiation myelopathy following single courses of radiotherapy and retreatment. Int J Radiat Oncol Biol Phys. 1994 Oct 15;30(3):575-81.
- Nieder C, Grosu AL, Andratschke NH, Molls M. Proposal of human spinal cord reirradiation dose based on collection of data from 40 patients. Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):851-5.
- Mithal NP, Needham PR, Hoskin PJ. Retreatment with radiotherapy for painful bone metastases. Int J Radiat Oncol Biol Phys. 1994 Jul 30;29(5):1011-4
- Kramer GW, Gans S, Ullmann E, van Meerbeeck JP, Legrand CC, Leer JW. Hypofractionated external beam radiotherapy as retreatment for symptomatic non-small-cell lung carcinoma: an effective treatment? Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1388-93
- Montebello JF, Aron BS, Manatunga AK, Horvath JL, Peyton FW. The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation. Am J Clin Oncol. 1993 Dec;16(6):482-8
- Gressen EL, Werner-Wasik M, Cohn J, Topham A, Curran WJ Jr. Thoracic reirradiation for symptomatic relief after prior radiotherapeutic management for lung cancer. Am J Clin Oncol. 2000 Apr;23(2):160-3.
- Lingareddy V, Ahmad NR, Mohiuddin M. Palliative reirradiation for recurrent rectal cancer. Int J Radiat Oncol Biol Phys. 1997 Jul 1;38(4):785-90
- Veninga T, Langendijk HA, Slotman BJ, Rutten EH, van der Kogel AJ, Prick MJ, Keyser A, van der Maazen RW. Reirradiation of primary brain tumours: survival, clinical response and prognostic factors. Radiother Oncol. 2001 May;59(2):127-37
- Kim HK, Thornton AF, Greenberg HS, Page MA, Junck L, Sandler HM. Results of re-irradiation of primary intracranial neoplasms with three-dimensional conformal therapy. Am J Clin Oncol. 1997 Aug;20(4):358-63
- Abdel-Wahab MM, Wolfson AH, Raub W, Landy H, Feun L, Sridhar K, Brandon AH, Mahmood S, Markoe AM. The role of hyperfractionated re-irradiation in metastatic brain disease: a single institutional trial. Am J Clin Oncol. 1997 Apr;20(2):158-60
- Deutsch M. Repeat high-dose external beam irradiation for in-breast tumor recurrence after previous lumpectomy and whole breast irradiation. Int J Radiat Oncol Biol Phys. 2002 Jul 1;53(3):687-91
- Russell AH, Koh WJ, Markette K, Russell KJ, Cain JM, Tamimi HK, Greer BE, Figge DC. Radical reirradiation for recurrent or second primary carcinoma of the female reproductive tract. Gynecol Oncol. 1987 Jun;27(2):226-32
- Beyer DC. Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology. 1999 Nov;54(5):880-3.
- Kumar PP, Good RR. Interstitial 125I implantation in the retreatment of retroperitoneal soft tissue sarcoma. Report of a case. Acta Radiol Oncol. 1986 Jan-Feb;25(1):37-9.
- De Crevoisier R, Bourhis J, Domenge C, Wibault P, Koscielny S, Lusinchi A, Mamelle G, Janot F, Julieron M, Leridant AM, Marandas P, Armand JP, Schwaab G, Luboinski B, Eschwege F. Full-dose reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy Institute in a series of 169 patients. J Clin Oncol. 1998 Nov;16(11):3556-62
- Kasperts N, Slotman B, Leemans CR, Langendijk JA. A review on re-irradiation for recurrent and second primary head and neck cancer. Oral Oncol. 2005 Mar;41(3):225-43.
- Schaefer U, Micke O, Schueller P, Willich N. Recurrent head and neck cancer: retreatment of previously irradiated areas with combined chemotherapy and radiation therapy-results of a prospective study. Radiology. 2000 Aug;216(2):371-6.
- Chua DT, Sham JS, Au GK. Induction chemotherapy with cisplatin and gemcitabine followed by reirradiation for locally recurrent nasopharyngeal carcinoma. Am J Clin Oncol. 2005 Oct;28(5):464-71.
- Oksuz DC, Meral G, Uzel O, Cagatay P, Turkan S. Reirradiation for locally recurrent nasopharyngeal carcinoma: treatment results and prognostic factors. Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):388-9
- Kramer NM, Horwitz EM, Cheng J, Ridge JA, Feigenberg SJ, Cohen RB, Nicolaou N, Sherman EJ, Babb JS, Damsker JA, Langer CJ. Toxicity and outcome analysis of patients with recurrent head and neck cancer treated with hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy from two prospective phase I and II studies. Head Neck. 2005 May;27(5):406-14
- Stephenson AJ, Eastham JA. Role of salvage radical prostatectomy for recurrent prostate cancer after radiation therapy. J Clin Oncol. 2005 Nov 10;23(32):8198-203
- Bianco FJ Jr, Scardino PT, Stephenson AJ, Diblasio CJ, Fearn PA, Eastham JA. Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys. 2005 Jun 1;62(2):448-53
- Stephenson AJ, Scardino PT, Bianco FJ Jr, DiBlasio CJ, Fearn PA, Eastham JA. Morbidity and functional outcomes of salvage radical prostatectomy for locally recurrent prostate cancer after radiation therapy. J Urol. 2004 Dec;172(6 Pt 1):2239-43
- Ward JF, Sebo TJ, Blute ML, Zincke H. Salvage surgery for radiorecurrent prostate cancer: contemporary outcomes. J Urol. 2005 Apr;173(4):1156-60.
- Bochner BH, Figueroa AJ, Skinner EC, Lieskovsky G, Petrovich Z, Boyd SD, Skinner DG. Salvage radical cystoprostatectomy and orthotopic urinary diversion following radiation failure. J Urol. 1998 Jul;160(1):29-33.
- Nakamura T, Hayashi K, Ota M, Eguchi R, Ide H, Takasaki K, Mitsuhashi N. Salvage esophagectomy after definitive chemotherapy and radiotherapy for advanced esophageal cancer. Am J Surg. 2004 Sep;188(3):261-6
- Urschel JD, Sellke FW. Complications of salvage esophagectomy. Med Sci Monit. 2003 Jul;9(7):RA173-80
- Wong LY, Wei WI, Lam LK, Yuen AP. Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck. 2003 Nov;25(11):953-9.
- Yom SS, Machtay M, Biel MA, Sinard RJ, El-Naggar AK, Weber RS, Rosenthal DI. Survival impact of planned restaging and early surgical salvage following definitive chemoradiation for locally advanced squamous cell carcinomas of the oropharynx and hypopharynx. Am J Clin Oncol. 2005 Aug;28(4):385-92.
- Mori Y, Kobayashi T, Kida Y, Oda K, Shibamoto Y, Yoshida J. Stereotactic Radiosurgery as a Salvage Treatment for Recurrent Skull Base Adenoid Cystic Carcinoma. Stereotact Funct Neurosurg. 2006 Jan 19;83(5-6):202-207
- Lee N, Millender LE, Larson DA, Wara WM, McDermott MW, Kaplan MJ, Sneed PK. Gamma knife radiosurgery for recurrent salivary gland malignancies involving the base of skull. Head Neck. 2003 Mar;25(3):210-6
- Chua DT, Sham JS, Kwong PW, Hung KN, Leung LH. Linear accelerator-based stereotactic radiosurgery for limited, locally persistent, and recurrent nasopharyngeal carcinoma: efficacy and complications. Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):177-83
- Xiao J, Xu G, Miao Y. Fractionated stereotactic radiosurgery for 50 patients with recurrent or residual nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2001 Sep 1;51(1):164-70.
- Pai PC, Chuang CC, Wei KC, Tsang NM, Tseng CK, Chang CN. Stereotactic radiosurgery for locally recurrent nasopharyngeal carcinoma. Head Neck. 2002 Aug;24(8):748-53.
- Wulf J, Hadinger U, Oppitz U, Thiele W, Ness-Dourdoumas R, Flentje M. Stereotactic radiotherapy of targets in the lung and liver. Strahlenther Onkol. 2001 Dec;177(12):645-55
- Poltinnikov IM, Fallon K, Xiao Y, Reiff JE, Curran WJ Jr, Werner-Wasik M. Combination of longitudinal and circumferential three-dimensional esophageal dose distribution predicts acute esophagitis in hypofractionated reirradiation of patients with non-small-cell lung cancer treated in stereotactic body frame. Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):652-8.
- Combs SE, Widmer V, Thilmann C, Hof H, Debus J, Schulz-Ertner D. Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM). Cancer. 2005 Nov 15;104(10):2168-73.
- Hudes RS, Corn BW, Werner-Wasik M, Andrews D, Rosenstock J, Thoron L, Downes B, Curran WJ Jr. A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma. Int J Radiat Oncol Biol Phys. 1999 Jan 15;43(2):293-8.
- Noel G, Proudhom MA, Valery CA, Cornu P, Boisserie G, Hasboun D, Simon JM, Feuvret L, Duffau H, Tep B, Delattre JY, Marsault C, Philippon J, Fohanno D, Baillet F, Mazeron JJ.Radiosurgery for re-irradiation of brain metastasis: results in 54 patients. Radiother Oncol. 2001 Jul;60(1):61-7
- Milker-Zabel S, Zabel A, Thilmann C, Schlegel W, Wannenmacher M, Debus J. Clinical results of retreatment of vertebral bone metastases by stereotactic conformal radiotherapy and intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):162-7.
- Mahan SL, Ramsey CR, Scaperoth DD, Chase DJ, Byrne TE. Evaluation of image-guided helical tomotherapy for the retreatment of spinal metastasis. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1576-83
- Gerszten PC, Burton SA, Quinn AE, Agarwala SS, Kirkwood JM. Radiosurgery for the Treatment of Spinal Melanoma Metastases. Stereotact Funct Neurosurg. 2006 Mar 8;83(5-6):213-221
- Gerszten PC, Burton SA, Ozhasoglu C, Vogel WJ, Welch WC, Baar J, Friedland DM. Stereotactic radiosurgery for spinal metastases from renal cell carcinoma. J Neurosurg Spine. 2005 Oct;3(4):288-95.
- Gerszten PC, Ozhasoglu C, Burton SA, Vogel WJ, Atkins BA, Kalnicki S, Welch WC. CyberKnife® frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery. 2004 Jul;55(1):89-98
- Gagnon GJ, Henderson FC, Collins BT, McRae JA. Chapter 16. Radiosurgery in previously irradiated spines. Robotic Radiosurgery. Volume 1. 2005.:161-169
- Bellairs EE, Fink AS. Chapter 30: Radiosurgery for recurrent pelvic tumors. Robotic Radiosurgery. Volume 1. 2005. 333-345
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:
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.