Historical Perspectives and Future Applications

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RADIOGUIDED SURGERY

HISTORICAL PERSPECTIVES AND FUTURE APPLICATIONS Fadi F. Haddad, MD, Steven C. Shivers, PhD, and Douglas S. Reintgen, MD

Human curiosity and the innate drive to learn and discover have pushed surgeons to seek continuously more accurate ways to diagnose and treat diseases. Moreover, physicians are in a continuous quest for procedures that are least morbid and associated with minimal amounts of psychological and somatic trauma. Ironically, it is the patient population that is driving these innovations and discoveries forward; patients are interested in procedures and medical tests that are less invasive and associated with few or no side effects. Since the discovery of x-rays in 1896 by Roentgen, many diagnostic and therapeutic techniques have been developed or discovered with the specific purpose of better serving the patient. Such a development was the introduction of minimally invasive surgery. This new approach to the surgical treatment of several illnesses such as symptomatic cholelithiasis, hiatal hernia, gastroesophageal reflux, and appendicitis has been shown to be extremely successful. A major part to the success of such procedures (e.g., laparoscopic cholecystectomy, laparoscopicNissen's fundoplication) lies in the fact that the morbidity sustained by the patient after such an operation is markedly reduced. Although no compromise in the overall outcome of the patient is made, the surgeon is able to provide a new therapeutic approach to common surgical illnesses. Large wounds and muscle splitting incisions, which are sources of pain, discomfort, paresthesia, and infections, are avoided. Postoperative ileus has been reduced

From the Department of Surgery, University of South Florida; and the H. Lee Moffitt Cancer Center, Tampa, Florida.

SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 8. NUMBER 3 . JULY 1999

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markedly and hospital stay has been shortened. Furthermore, marked cost savings were demonstrated with certain procedures (i.e., laparoscopic cholecystectomy).4Hence, minimally invasive surgery became a backbone in the surgical armamentarium and will remain as a valuable addition. A recent application of minimally invasive surgery is the development of lymphatic mapping and sentinel lymph node (SLN) biopsy. This newest field in surgery was brought about by the necessity to better stage melanoma patients. As with other solid tumors, the single most powerful predictor of survival of melanoma patients is the presence or absence of regional lymph node metastasis. When compared with patients with no evidence of nodal metastasis, patients with metastatic disease in their regional nodes have a 40% lower 5-year survival rate.6Furthermore, when metastasis to the regional lymph nodes occurs, the prognostic factors derived from the primary tumor lose their importance. Based on these findings, the concept of an orderly progression of melanoma was i n t r ~ d u c e d . ~ ~ , ~ ~ The thicker the tumor, the greater the likelihood for regional nodal metastasis. Furthermore, distant metastasis does not occur in the absence of regional disease. The belief is if the surgeon performs a prophylactic elective lymph node dissection (ELND) on a melanoma patient who does not have distant metastasis, a potential cure could be achieved. Four prospective randomized trials were conducted to answer this q u e s t i ~ n . ~ , ~ ~ , ~ However, three of the trials had significant design flaws that rendered any objective interpretation of the results difficult. These early trials are hampered by the fact that little or no microstaging of the primary tumor was performed and lymphoscintigraphy was not used to identify all the basins at risk for disease. The designed study was the Intergroup Melanoma Trial headed by Dr. Charles Balch that included intermediate thickness melanoma patients with clinically negative nodes. Patients on this trial were allocated randomly either to receive an ELND or for observation. These patients were stratified for major prognostic factors, including tumor thickness, primary site, and presence or absence of ulceration. All patients underwent a preoperative lymphoscintigraphy to identify all nodal basins at risk for metastatic disease. The importance of such an approach was based on demonstrating that lymphoscintigraphy is an accurate method of identifying all nodal basins at risk for metastatic disease and unless performed preoperatively, the ELND may be misdirected in up to 50% of the cases.31 With lymphoscintigraphy,investigators are able to identify in-transit areas of nodal collections as well as all nodal basins at risk for metastatic melanoma. This is especially useful when the primary lesion involves watershed areas of the body such as the trunk, head, and neck regions. These results show that lymphoscintigraphy can be used as a road map so the surgeon does not perform too little or too aggressive surgery. The overall survival in the Intergroup Melanoma Trial for the ELND tended toward an increased survival but did not reach statistical significance ( P = 0.20); however, on subset analysis, a subgroup of patients did benefit from ELND. Those patients who are 60 years of age or younger with a tumor

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thickness of 1.1to 2 mm had an improvement in 5-year survival rate with ELND compared with observation (96%versus 84%; P = 0.007). Of interest at the time when the results of the Intergroup were being unfolded, a new procedure was being developed at the John Wayne Cancer Institute. Led by the pioneering work of Donald Morton and his group, the technique of intraoperative lymphatic mapping and selective lymphadenectomy was i n t r ~ d u c e dThe . ~ ~concept of this procedure is based on the fact that areas of the skin have specific patterns of lymphatic drainage not only to the regional nodal basin but also to specific lymph nodes in that basin. Whereas Cabanas8 introduced this concept in 1977 in the treatment of penile cancer (Fig. I), Morton introduced the use of a vital blue dye or isosulfan blue in the search for the first SLN. He developed a feline model to examine the patterns of the cutaneous lymphatic drainage and the identification of the SLN in a regional basin that drains a specific skin site. Of interest, cats have on average three nodes in each groin. Intraderma1 injection of the medial thigh with isosulfan blue agent resulted in the coloring of the central node only, whereas intradermal injection of the abdomen or lateral thigh resulted in the staining of the lateral node only and the intradermal injection of the perineum resulted in the staining of the medial node. These findings confirmed the hypothesis that specific areas of the skin drain to specific nodes in a consistent fashion.

ANATOMY AND BIOPSY OF SENTINEL LYMPH NODES

Figure 1. A, Title page of Ramon M. Cabanas', MD, manuscript published in 1977, describing the concept of the sentinel lymph node in penile cancer. B, In his original manuscript,Cabanas describes certain nodes in the superficial groin that receive direct lymphatic flow from the primary site on the penis.

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After these findings, Donald Morton et aP5performed intraoperative lymphatic mapping and SLN dissection using isosulfan blue dye in 223 patients. All patients underwent a completion regional lymphadenectomy after the SLN biopsy. The histologic status of the dissected nodal basin was compared with the histologic status of the SLN. One hundred ninetyfour patients out of 223 had a successful mapping (82%).In 192 of 194 patients who had a successful lymphatic mapping, the SLN histologic status predicted the histologic status of the dissected basin. There were only 2 patients whose SLN had no evidence of melanoma but had melanoma in non-SLNs. These findings support the concepts that defined patterns of lymphatic drainage allow the identification of the SLN and that the absence of melanoma in the SLN accurately predicts the absence of metastatic disease in the higher regional basin nodes. Krag and his group then performed a pilot study using technetiumlabeled colloid as a mapping agent.3 The SLNs were identified using a hand-held gamma probe. They successfully identified a SLN in all ten patients. Thereafter, the H. Lee Moffitt Cancer Center group achieved the highest success rates for the identification of the SLN with a suitable learning curve in large trials by using a combination of isosulfan blue and radiocolloid as mapping agents.' This group believes that both mapping techniques are complementary because one is visual (quantitative) and the other is auditory (qualitative). With the addition of the intraoperative technetium-labeled sulfur colloid mapping to the isosulfan blue mapping agent, investigators at H. Lee Moffitt Cancer Center were able to render this technique more reliable and more widely applicable. They were also able to shorten the learning curve, rendering this procedure more reproducible. Since then, several investigators showed a mapping success rate as high as 96%to 100%;they also confirmed that the histology of the SLN reflected the true histologic status of the nodal b a ~ i n . ' ~ , ' ~ , ' ~ , ~ ~ Once the SLN is harvested, a detailed examination is performed using serial sectioning of the node, hematoxylin and eosin (H&E) and immunohistochemical staining with specific monoclonal antibodies (S-100 and HMB-45), and reverse transcriptase polymerase chain reaction (RT-PCR) determination. The RT-PCR technique is a more sensitive assay that allows the discovery of smaller volumes of disease. In fact, RT-PCR assays resulted in the discovery of micrometastases in patients with melanoma43 and breast cancer15,26,28,31,39,M,45 when the results of routine histologic examination of the regional lymph nodes were negative. Preliminary findings suggest that patients with melanoma who were found to have histologically negative SLNs but positive SLNs by tyrosinase RT-PCR had a poorer outcome when compared with patients who have no evidence of nodal metastatic disease detected by either e ~ a m i n a t i o nThis . ~ ~ single institution study of the clinical value of RT-PCR assay in melanoma is currently being evaluated in a prospective, randomized, multicenter, national study, the Sunbelt Melanoma Trial. Early detection of occult metastases using the intraoperative mapping and SLN dissection identifies a group of patients who are at high risk of

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recurrent metastatic disease and may benefit from adjuvant therapy such as interferon alpha-2b. In other words, SLN mapping serves as a valuable staging procedure and provides important prognostic information. However, removal of regional lymph nodes that contain occult foci of metastatic melanoma may or may not improve survival per se; this controversy will be resolved once the results of the Multicenter Sentinel Lymphadenectomy Trial are out. This trial is randomizing patients with melanoma larger than 1 mm in Breslow thickness to either a wide local excision and observation of the regional basin (s) or wide local excision and SLN biopsy. Patients with a positive SLN will go on to have a complete lymph node dissection (CLND).The end-point of this trial is whether there is a survival advantage with the surgical strategy. Encouraged by the successful results with melanoma, investigators were quick to try to incorporate the technique of lymphatic mapping and SLN biopsy into the treatment of several other solid tumors. The H. Lee Moffitt Cancer Center group successfullyapplied this technology in treating Merkel cell carcinoma, poorly differentiated squamous cell carcinomas of the skin, and metastatic bone cancer.34Furthermore, several small clinical trials were conducted prospectively and revealed that lymphatic mapping and SLN biopsy can be incorporated safely in the treatment of Merkel cell or squamous cell carcinomasz4as well as vulvar,2O vaginal, and penileT4 cancers, perhaps eventually avoiding the routine bilateral groin dissection and its resultant morbidity. Investigators recently have applied minimally invasive radioguided surgery to the treatment of primary hyperparathyroidism using sestamibi as a mapping agent.7,21,22 They reported an 80% to 88% success rate in identifying a single parathyroid adenoma,3O which resulted in primary hyperparathyroidism. The sestamibi scan has a sensitivity of approximately 90% and a specificity approaching 100% in identifying patients with a single adenoma. Moreover, a pilot study is currently being conducted at the H. Lee Moffitt Cancer Center to evaluate the application of lymphatic mapping and SLN biopsy in the treatment of patients with colorectal cancer. The purpose of this study is (1) to confirm that this technique is feasible in this group of patients and (2) to achieve a more accurate staging. By identifying the SLN and subjecting it to a more detailed pathologic examination, it is hypothesized that a more accurate staging will be accomplished. This group of patients, upstaged to stage 111, will be then candidates for adjuvant chemotherapy. Similar work is This group had 30 also being conducted at Michigan State Uni~ersity.~~ consecutive patients with proven or suspected colorectal cancer who underwent an intraoperative subserosal injection of Lymphazurin. Within a few minutes, the SLN were identified and harvested. The SLN were successfully identified in 29 of 30 patients (97%).Eight patients had positive nodes, which were the only site of metastasis in five patients. In all negative SLNs, other lymph nodes were also negative. Hence, the false-negative rate was 0%. The application of this new technique that has the most interest may be in the treatment of early breast cancer. Attempting to duplicate the

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success of lymphatic mapping and SLN biopsy in the treatment of malignant melanoma, Giuliano et all2 from the John Wayne Cancer Institute introduced this technique in 1994 for the treatment of early breast cancer. Whereas Giuliano et a1 used solely a vital blue dye as a mapping substance, Krag et alls used radiocolloid in their initial breast cancer mapping trial. Their initial success rates in identifying the SLN were 65% and 71%, respectively. By combining both mapping techniques, investigators at the H. Lee Moffitt Cancer Center2were able to achieve a success rate of 92% in their first 62 patients. Since then, several series were published9,n,16,23,27,36,42; the success rate of the mapping ranged from 66% to loo%, and the rate of skip metastasis ranged from 0% to 12.5%.A skip metastasis is defined as a SLN that is negative for metastatic disease while higher echelon axillary nodes are found to harbor metastatic disease. In a recent update of the data from the H. Lee Moffitt Cancer Center, which includes data for several surgeons: 700 patients with breast cancer underwent lymphatic mapping using both techniques as described earlier. The following results were obtained: (1)the rate of SLN identification was 95%, (2) the average number of SLN per patient was 2.02, (3) total number of harvested SLNs was 1348, with 238 being positive, and (4) the percent of patients with positive SLNs was 26.5%.Of these 1348 SLNs, 30.1%were blue only, 42.1% were hot only, and 27.8% were both. These findings again confirm that both techniques are complementary. With the blue dye mapping the surgeon can have a visual confirmation of the presence of a SLN. With the radiocolloid mapping, the surgeon is able to direct the dissection through the axilla using the hand-held gamma probe, minimizing tissue disruption. Moreover, the surgeon can conclude safely the search for the SLN once the basin count returns to the background count level. This is not feasible if vital blue dye is used alone in mapping. The technique of lymphatic mapping and SLN biopsy in breast cancer is gaining popularity because it provides a more accurate staging associated with a marked reduction of morbidity that is usually seen with complete axillary nodal dissection, namely drain discomfort, prolonged hospitalization, acute and chronic lymphedema, and paresthesia. Moreover, the added cost of radioguided and blue dye lymphatic mapping is offset by the reduction in the rate of CLND performed (from 100% to 26%) as well as savings in hospital costs because of the outpatient surgery that is performed. Furthermore, the long-term benefits of reducing the occurrence of lymphedema and its morbidity also should reduce the overall costs. Despite growing demands from the patients for a rapid implementation of lymphatic mapping and SLN biopsy in the routine treatment of breast cancer, the medical community, especially surgeons, should resist the temptation to abandon the CLND. It is important to note that in all published series so far, the procedure was performed by a small group of highly experienced breast surgeons who for the most part are pioneering this new technique. We recommend that lymphatic mapping and SLN biopsy in the treatment of breast cancer should be carried out in the con-

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text of large prospective multicenter clinical trials until we (1) identify the correct rates of successful mapping and skip metastasis, (2) define better the nuclear medicine, surgical, and pathologic aspect of this procedure, and (3) better define the population of patients who would benefit from it. With the achievement of these goals, lymphatic mapping and SLN biopsy will become the standard of care, bringing about the third major evolution in the surgical treatment of breast cancer, after the introduction of the radical mastectomy and later breast conservation therapy. Lymphatic mapping and SLN biopsy is a new technique that soon will be incorporated into the armamentarium of the general surgeon. It has a vast array for its application. More than 350,000 new cancer cases (Table l ) l 9 are diagnosed yearly for which this procedure has potential applications. However, it should be noted that as with any new technology or procedure, a great deal of investigation and evaluation should be conducted before recommending it as the standard of care. This is why it is of utmost importance to conduct well-designed multicenter prospective and preferably randomized trials in the hope of answering crucial questions regarding the feasibility, safety, reproducibility, and benefits of such a technique. Furthermore, as this new technique is introduced in the surgical community, questions are arising as to who should be performing the procedure and what is required for the credentialing of the surgeon and the medical i n s t i t ~ t i o nWhereas .~~ hospital committees usually handle the credentialing of their staff, it is becoming more evident that the American College of Surgeons, the Society of Surgical Oncology, and other national organizations are increasingly being more involved in formulating guidelines for surgeons and hospitals to follow. The hope is to avoid the mistakes made during the credentialing of surgeons with the laparoscopic technique. The American Society of Breast Surgeons published a position paper at the 84th Clinical Congress of the American College of Surgeons' meeting (October 1998) in the midst of defining the recommendations for the certification of surgeons. Attending a formal minimally invasive Table 1. PRIMARY CANCERS TO WHICH SLN BIOPSY CAN BE APPLIED Tumors

melanoma breast Merkel cell carcinoma squamous cell carcinoma parathyroid adenoma bone tumors vulvar tumors cervical tumors colon cancers rectal cancers anal cancers

Total

Estimated Number for 1999

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course, usually required by a hospital credentialing committee, is not sufficient to credential a surgeon; the surgeon should perform initial cases under the guidance of a credentialed surgeon in this technique. For breast cancer, the surgeon should achieve at least a minimum of 30 cases in which he or she performs a complete node dissection regardless of the SLN status. The purpose of doing so is to determine the success rate of the lymphatic mapping and the rate of skip metastasis. For example, the training surgeon should be able to find an axillary SLN in at least 85% of breast cancer patients and a rate of skip metastasis of 1%to 2% in the first 10 patients with metastatic disease. Any results short of these standards may suggest that the surgeons has not yet mastered the technique and should not proceed with lymphatic mapping and SLN biopsy without complete node dissection. Minimally invasive surgery in general and lymphatic mapping and SLN biopsy in particular will bring about a major evolution and revolution in the surgical field. However, until then it should be clear in our minds that safety, efficacy, and benefit of lymphatic mapping and SLN biopsy as a replacement of standard treatment procedures should be evaluated thoroughly in the context of well-designed prospective, randomized trials. The American College of Surgeons and the National Surgical Adjuvant Breast and Bowel Project are currently designing two separate trials to assess the role of SLN biopsy in the treatment of breast cancer. The Melanoma Sentinel Lymphadenectomy Trial is being conducted to assess the role of SLN biopsy in the treatment of melanoma. The results of these trials will not be available before 5 to 10 years. In the meantime, clinicians and investigators are urged to continue in their quest for improving and refining this new technique.

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Address reprint requests to Douglas S. Reintgen, MD Cutaneous Oncology Program H. Lee Moffitt Cancer Center and Research Institute 12902 Magnolia Drive Tampa, FL 33612-9497 e-mail: [email protected]