Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

Anal sphincter conservation for patients with adenocarcinoma of the distal rectum: long-term results of radiation therapy oncology group protocol 89-02.

PURPOSE: To assess the outcome of a multi-institutional, national cooperative group study attempting functional preservation of the anorectum for patients with limited, distal rectal cancer. METHODS AND MATERIALS: Between September 21, 1989 and November 1, 1992, a Phase II trial of sphincter-sparing therapy was conducted for patients with clinically mobile rectal cancers located below the pelvic peritoneal reflection. Protocol treatment was designed for patients who were, in the judgement of their attending surgeon, unsuitable for anal sphincter conservation in the context of anterior resection, and would have required abdominoperineal resection (APR) as conventional surgical therapy. Primary cancers were estimated to be 4 cm or less in largest clinical diameter, and occupied 40% or less of the rectal circumference. Chest radiography and computerized axial tomography (CT) of the abdomen and pelvis excluded patients with overt lymphatic or hematogenous metastases. Protocol surgery was intended to remove the primary cancer by en-bloc, transmural excision of an ellipse of rectal wall by transanal, transcoccygeal, or trans-sacral technique, while conserving the anal sphincter. Based on tumor size, T classification, grade, and adequacy of surgical margins, patients were allocated to one of three treatment assignments: observation, or adjuvant treatment with 5-fluorouracil (5-FU) and one of two different dose levels of local-regional radiation. After completion of protocol therapy, patients were observed with follow-up that included periodic general physical and rectal examination, determinations of CEA, abdominopelvic CT, chest radiography, and surveillance endoscopy. Sixty-five eligible and analyzable patients were registered. RESULTS: With minimum follow-up of 5 years and median follow-up of 6.1 years, 11 patients have failed: 3 patients recurred local-regionally only, 3 patients had distant failure alone, and 5 patients manifested local-regional and distant failure. Eight patients died of intercurrent illness. Local-regional failure correlated with T-category revealed: T1 1/27 (4%), T2 4/25 (16%), and T3 3/13 (23%). Local-regional failure escalated with percentage involvement of the rectal circumference: 2/31 (6%) among patients with cancers involving 20% or less of the rectal circumference, and 6/34 (18%) among patients with cancers involving 21-40% of the circumference. Distant dissemination rose with T-category with 1/27 (4%) T1, 3/25 (12%) T2, and 4/13 (31%) T3 patients manifesting hematogenous spread. Eight patients (12%) required temporary or permanent colostomy. Five of 8 patients with local-regional recurrence achieved local-regional control with management including surgery, although 4 of these patients subsequently developed distant dissemination. Three patients (5%) had persistent, uncontrolled, local disease. Actuarial freedom from pelvic relapse at 5 years is 88% based on the entire study population, and 86% for the less favorable patients treated with adjuvant radiation and 5-FU. CONCLUSION: Conservative, sphincter-sparing therapy is a feasible alternative treatment for selected patients with limited cancer involving the middle and lower rectum. Risk of both local and distant failure appears to escalate with increasing T-category (depth of invasion). Results achieved in the multi-institutional, cooperative group setting approximate results reported from single institutions.

Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant radiotherapy.

PURPOSE: To analyze patterns of failure in malignant melanoma patients with lymph node involvement who underwent complete lymph node dissection (LND) of the nodal basin. To determine prognostic factors predictive of local recurrence in the lymph node basin in order to select patients who may benefit from adjuvant radiotherapy. METHODS AND MATERIALS: A retrospective analysis of 338 patients undergoing complete LND for melanoma between 1970 and 1996 who had pathologically involved lymph nodes was performed. Mean follow-up from the time of LND was 54 months (range: 12-306 months). Lymph node basins dissected included the neck (56 patients), axilla (160 patients), and groin (122 patients). Two hundred fifty-three patients (75%) underwent therapeutic LND for clinically involved nodes, while 85 patients (25%) had elective dissections. Forty-four percent of patients received adjuvant systemic therapy. No patients received adjuvant radiotherapy to the lymph node basin. RESULTS: Overall and disease-specific survival for all patients at 10 years was 30% and 36%, respectively. Overall nodal basin recurrence was 30% at 10 years. Mean time to nodal basin recurrence was 12 months (range: 2-78 months). Site of nodal involvement was prognostic with 43%, 28%, and 23% nodal basin recurrence at 10 years with cervical, axillary, and inguinal involvement, respectively (p = 0.008). Extracapsular extension (ECE) led to a 10-year nodal basin failure rate of 63% vs. 23% without ECE (p < 0.0001). Patients undergoing a therapeutic dissection for clinically involved nodes had a 36% failure rate in the nodal basin at 10 years, compared to 16% for patients found to have involved nodes after elective dissection (p = 0.002). Lymph nodes larger than 6 cm led to a failure rate of 80% compared to 42% for nodes 3-6 cm and 24% for nodes less than 3 cm (p < 0.001). The number of lymph nodes involved also predicted for nodal basin failure with 25%, 46%, and 63% failure rates at 10 years for 1-3, 4-10, and > 10 nodes involved (p = 0.0001). There was no significant difference in nodal basin control in patients with synchronous or metachronous lymph node metastases, nor in patients receiving or not receiving adjuvant systemic therapy. Nodal basin failure was predictive of distant metastasis with 87% of patients with nodal basin recurrence developing distant disease compared to 54% of patients without nodal failure (p < 0.0001). On multivariate analysis, number of positive nodes and type of dissection (elective vs. therapeutic) were significant predictors of overall and disease-specific survival. Size of the largest lymph node was also predictive of disease-specific survival. Site of nodal involvement and ECE were significant predictors of nodal basin failure. CONCLUSIONS: Malignant melanoma patients with nodal involvement have a significant risk of nodal basin failure after LND if they have cervical involvement, ECE, >3 positive lymph nodes, clinically involved nodes, or any node larger than 3 cm. Patients with these risk factors should be considered for adjuvant radiotherapy to the lymph node basin to reduce the incidence of nodal basin recurrence. Patients with nodal basin failure are at higher risk of developing distant metastases.

Postoperative radiotherapy for malignant fibrous histiocytoma.

Between 1974 and 1989, 49 patients with histologically confirmed malignant fibrous histiocytoma received postoperative radiotherapy at the Mallinckrodt Institute of Radiology for primary (41) or recurrent (8) disease. Median age of the patients was 63 years, and the median follow-up period was 41 months. Patients were grouped according to the 1988 AJC staging classification: stage IA (one patient), stage IIA (4 patients), stage IIB (9 patients), stage IIIA (15 patients), stage IIIB (18 patients), and stage IVA (2 patients). Eight tumors (16%) were in the pelvis, 8 (16%) in the trunk, 4 (8%) in the head and neck, and 29 (60%) in the extremities. Primary surgical procedures included incisional biopsy (4 patients), excisional biopsy (19), narrow margin excision (14), wide local excision (9), and removal of the entire compartment (3). Based on pathology reports, the margins of resection were classified as positive in 23 (5 gross, 18 microscopic), 5 close, 11 negative, and 10 unknown. Patients were irradiated with shrinking field technique; the median radiation dose was 6000 cGy, with more than 95% of patients receiving at least 4500 cGy. In addition, seven patients received postoperative chemotherapy. The 5-year overall survival rate was 62%, disease-free survival 64%, local control 68%, and freedom-from-distant metastasis 85%. Thirteen patients had local recurrences, with greater than 75% recurring within 3 years. Sites of local recurrence were as follows: trunk (3), pelvis (3), lower extremities (4), and head and neck (3). There appears to be a correlation of local failure with positive surgical margin: of 23 patients with positive margins, 9 (39%) had local recurrences, whereas 1 of 11 patients (9%) with negative margins had local recurrence. Three of 13 patients with persistent or recurrent disease were salvaged by additional treatment, rendering ultimate local control in 80% (39/49). Thirty-four of 36 patients with local control obtained good to excellent function. Two patients were found to have grade 3 complications: 1 patient had edema of the extremity, and the other developed necrotic skin ulcer that was successfully treated with hyperbaric oxygen. Five patients developed distant metastases, with 80% occurring within 2 years. In summary, adequate but conservative surgery with postoperative radiotherapy for malignant fibrous histiocytoma can achieve local tumor control as well as preservation of functional limbs with acceptable morbidity in a large proportion of patients.

Management of soft tissue sarcomas of the extremities.

The management of soft tissue sarcomas has undergone and continues to undergo important changes. The purpose of this report is to review the presentation, diagnosis, and natural history of soft tissue sarcomas. In so doing, the importance of a careful and rigorous method of evaluation will be emphasized. Furthermore, the results of multidisciplinary treatment, with a goal towards limb salvage, will be reviewed. With appropriate and timely intervention, selected patients with pulmonary metastases may still experience long-term survival. Throughout this review, the importance of early and continuing multidisciplinary treatment and evaluation will be emphasized.

Long-term results of surgical resection of locally advanced colorectal carcinoma.

This study was undertaken to review the long-term results of multivisceral resection of locally advanced colorectal carcinoma. Between 1964 and 1980, 1042 patients underwent exploratory surgery for colorectal cancer. Of these, 58 patients (5.5%) underwent curative multivisceral resection for suspected contiguous invasion by the primary tumor. Follow-up was complete for all patients. The primary tumors were located in the rectum (38 patients), sigmoid (9 patients), left colon (6 patients), and right colon (5 patients). En bloc resection of other viscera included uterus, adnexa, bladder, vagina, small intestine, abdominal wall, liver, stomach, kidney, and ureter. The operative morbidity and mortality rates were 31% and 1.7%, respectively. Resection margins were free of tumor in 54 patients. In the four patients with tumor-positive resection margins, recurrence of disease was evident between 8 and 22 weeks after surgery (mean survival time, 8.2 months). Carcinomatous invasion of the resected contiguous organ was confirmed in 49 patients (84%). The mean survival time for patients without lymph node metastases was 100.7 months, but it was only 16.2 months (p less than 0.01) for patients with lymph node metastases. Actuarial 5-year disease-free survival rate for patients without lymph node metastases was 76% (36 of 47 patients). None of the patients (0 of 11) with lymph node metastases survived for 5 years. Three of 36 of the 5-year survivors experienced recurrence of disease before the seventh postoperative year; no cancer-related deaths occurred between 7 and 25 years. These data suggest that survival in locally advanced colorectal carcinoma is more dependent on lymph node status than on the extent of local invasion. Effective disease control associated with survival in the long term can be achieved by multivisceral resection.

Exenterative surgery for locally advanced rectosigmoid cancers. Is it worthwhile?

Among 1480 patients treated for cancers of the rectosigmoid over a 30-year period, 24 patients underwent total pelvic exenteration. These patients, 13 men and 11 women, had a median age of 64 years. Pathologic staging revealed 15 Dukes' B and nine Dukes' C lesions. For 17 patients, this operation was the only form of therapy. The operative mortality rate was 20.8%; however, the mortality rate has decreased to 13.3% during the past 20 years and to 9% in the past decade. Five complications occurred in the group surviving the procedure, resulting in a 26.3% morbidity rate. Three of the five complications occurred in patients who had previous radiation therapy or surgery. The overall 5-year survival rate was 41.6%. Those patients surviving the operation had 5- and 10-year survival rates of 52.6% and 31.5%, respectively. There were seven patients in whom the disease recurred at an average of 20.3 months after exenteration, and all died an average of 8 months later. The recurrence rate for patients with Dukes' B lesions was 27% compared with 57% for patients with Dukes' C lesions. The remaining 12 disease-free patients had a mean survival of 11 years. At present, four patients are alive and well 6 to 30 years after exenteration. The best predictor of morbidity was treatment before exenteration (p less than .005). Age older than 65 years and the presence of nodal metastases may contribute to increased mortality rates and recurrence, respectively, but these relationships were not statistically significant for the group. Total pelvic exenteration is advocated for selected primary, locally advanced, rectosigmoid lesions in good-risk patients; it can be achieved now with acceptable morbidity and mortality rates and a survival rate in excess of 40% at 5 years.

Radical resection of tumors of the inferior vena cava with vascular reconstruction and kidney autotransplantation.

BACKGROUND: Tumors of the inferior vena cava (IVC) are rare tumors. Although often locally confined, juxtaposed vital structures usually limit the extent of resection. However, complete surgical resection has been shown to be the most important positive prognostic factor. METHODS: Four patients had resection of primary vena caval tumors. In two patients with locally extensive vena caval tumors the limits of conventional resection were extended by means of complete resection of the involved infrahepatic IVC, aorta, and both kidneys. The IVC and aorta were reconstructed with synthetic grafts, and the uninvolved kidney was autotransplanted for both patients. RESULTS: Of the two patients treated with more extensive resection, one patient had no evidence of disease 26 months after operation, and the second patient died of recurrent disease 23 months after operation. CONCLUSIONS: Primary tumors of the IVC may extend locally without distant metastasis. Radical surgical excision as the primary mode of treatment provides the best chance for prolonged survival in appropriately selected patients with tumors of the IVC. After surgical excision the patient with the leiomyosarcoma was treated with radiation therapy and the patient with rhabdomyosarcoma by chemotherapy. Although leiomyosarcomas of the IVC are rare tumors, the first patient is only the third reported case of the even rarer rhabdomyosarcoma of the IVC.

Evolution of sentinel lymph node biopsy for melanoma at a National Cancer Institute-designated cancer center.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has rapidly evolved into the standard of care for clinically node-negative melanoma. Since adopting sentinel lymph node (SLN) technology in 1993, we have periodically reviewed our institution's results and made several modifications. METHODS: From January 1993 to December 1998, 182 patients with clinically node-negative primary cutaneous melanoma underwent SLNB. Charts were retrospectively reviewed and assessed for the technique for the identification of the SLN, the pathologic analysis, and the use of intraoperative frozen section. RESULTS: The accuracy of SLN identification improved from 91% to 100% with the combination of isosulfan blue dye and radiolabeled colloid over isosulfan blue dye alone. Routine versus selective lymphoscintigraphy identified 7 in-transit SLNs and increased detection of dual nodal basin drainage (15%-27%). Identification of micrometastases in the SLN increased from 14% to 24% after a modification of pathologic evaluation. The positive SLN was the only involved node in most patients (80%). Intraoperative frozen section had a sensitivity of 58% and was of benefit in only 13 of 124 patients (10%). CONCLUSIONS: Several modifications to the identification of the SLNs and the detection of metastatic melanoma have improved our outcome with SLNB. A careful, periodic review of results to identify areas for improvement at each institution is crucial to the success of SLNB for melanoma.

1991 national survey of carcinoma of the breast by the Commission on Cancer.

A nationwide survey of patterns of care for carcinoma of the breast was conducted by the Commission on Cancer of the American College of Surgeons. Information regarding patient history, diagnostic tests, treatment, survival and disease status was obtained for 17,295 patients treated during 1983 and 24,356 patients treated during 1990. The results indicate that patients diagnosed in recent years (1990) are being treated at an earlier stage of the disease compared with the 1983 survey and the findings of earlier years, probably because of the use of mammography. Surgical treatment for conservation of the breast is being used more frequently, but modified radical mastectomy remains the most commonly used surgical treatment.

Large, deep high-grade extremity sarcomas: when is a myocutaneous flap reconstruction necessary?

The surgical treatment of large, deep high-grade extremity soft tissue sarcomas frequently produces a significant tissue defect. In addition, the management of the surgical wound is often further complicated by preoperative radiation or adjuvant therapies. The use of either pedicled or free myocutaneous flaps allows for more rapid and predictable wound healing in this situation. Myocutaneous flaps provide well-vascularized coverage of lost tissue volume, exposed vital structures, and prosthetic reconstruction materials. When harvested from unirradiated sites, flap coverage can overcome the detrimental effects of radiation therapy and chemotherapy on postoperative wound healing. Reconstruction of the soft tissue defect may also improve patient satisfaction with aesthetic issues. The use of innervated myocutaneous flaps can even address the functionality of the extremity following resection of major muscle groups. Myocutaneous flaps are an extremely versatile option for reconstruction in the treatment of large, deep high-grade extremity soft tissue sarcomas.

Multimodal therapy in locally advanced breast carcinoma.

Among 879 patients treated for breast cancer between 1975 and 1984, advanced disease was found in 125 (14%). A subgroup of 34 (4%) presented with untreated locally advanced disease without demonstrable distant metastases at the time of diagnosis (stage IIIB = T4abed, NX-2,MO). During the first 5 years (1975 through 1979), 17 patients were treated primarily with sequential radiotherapy and chemotherapy (Group A). From 1980 to 1984 (Group B), the management consisted of four courses of induction multi-drug chemotherapy followed primarily by mastectomy and additional chemotherapy. The mean follow-up for the most recent group (Group B) is 48 months. Follow-up was complete. While the local disease control rate was the same for both groups (76%), the survival was remarkably different. Group A patients experienced a median survival of 15 months, and only one survived 5 years. In Group B, the median survival was 56 months with nine patients (53%) alive between 40 and 76 months, seven (41%) of whom are 5-year survivors. While the overall mortality of patients with inflammatory breast cancer was greater in both groups when compared with the group with noninflammatory disease, the survival of patients in Group B was better than in Group A for both inflammatory and noninflammatory cancers (p less than 0.01). Estrogen receptor, nodal, and menopausal status did not influence survival. These data suggest that neoadjuvant chemotherapy improves survival for patients with stage IIIB breast carcinoma and delays the establishment or progression of distant metastases. Mastectomy is an important component in the treatment of this disease.

Reconstructive surgery for the complications of pelvic irradiation.

Severe damage to the pelvic viscera is a complication of irradiation therapy that, unfortunately, cannot always be avoided. Resulting rectal and rectocolonic strictures, rectovaginal fistulas, and shortening and stenosis of the vagina present very difficult problems that frequently require a colostomy for relief and may permanently impair sexual function. The authors present a new approach to correction of these unfortunate lesions based on the use of proximal nonirradiated colon which serves as a vascular pedicle graft to correct the defect without a complicated and massive resection. Twenty-two such operations have been done with 19 satisfactory to excellent results and two total failures (one death from small bowel complications). All patterns and combinations of irradiation injury have been found amenable to this technique of repair. These have included both web and linear strictures with and without fistulas. In half of the patients, it was possible to make use of normal colon bypassed by a prior colostomy. Normal nonirradiated colon with good blood supply will heal satisfactorily to irradiated colon or rectum, thus making excision of all the irradiated tissue unnecessary. The results of this surgical approach have thus far been gratifying and warrant further trials for these distressing injuries.

Local excision of rectal carcinoma.

The purpose of this study was to identify the recurrence rate, the salvage rate after recurrence, and the overall survival after local excision of rectal adenocarcinomas. A retrospective medical chart review was performed in 31 consecutive patients with rectal adenocarcinoma who underwent local excision at Roswell Park Cancer Institute from January 1990 through December 1999. After excision nine patients were excluded from further analysis because they were found to have advanced stage on pathologic examination (T2 primary tumors with vascular invasion or T3 tumors). Eight of the nine patients underwent abdominoperineal resection as definitive therapy. In the remaining 22 patients who underwent transanal excision as definitive surgical therapy there were 13 patients with T1 tumors and nine patients with T2 tumors. Overall seven patients (32%) developed local recurrences after local excision. This included four patients with T1 and three patients with T2 primary tumors. All recurrences occurred in the seven patients who did not receive adjuvant chemoradiation. All patients underwent salvage resection of the recurrence. Four patients who underwent salvage resection of the recurrence remain without evidence of disease at a median follow-up of 19.5 months. Local excision without adjuvant therapy has an unacceptably high rate of local recurrence. Although most patients who recur locally are salvaged by radical resection the long-term results after resection remain unknown. The use of adjuvant chemoradiation appears to reduce this high recurrence rate and may eventually become a standard adjunct to local excision of rectal cancer.

The current role of ultraradical surgery in the treatment of pelvic cancer.

Based on the results of experience accumulated in the past 30 years, exenterative pelvic surgery should be a part of the armamentarium of specially prepared oncologic surgeons. It is most frequently indicated for radiation failures in the treatment of carcinoma of the cervix, although it may be justified as primary treatment of selected cases of stage IV lesions without evidence of dissemination outside the pelvis. It is also justified for postirradiation radionecrosis causing sloughing and fistula, provided adequate relief cannot be offered by simple urinary and fecal diversion. For carcinoma of the rectum and pelvic colon, exenteration has a role in the advanced lesions that appear not to have become disseminated outside the pelvis but that involve contiguous viscera. Reoperation for recurrent carcinoma of the rectum is rarely successful, and this dreaded complication is best avoided by a well-planned and adequate standard first operation, or by the early recognition that a more extended operation is necessary. It is to be hoped that adjuvant radiation therapy, either preoperative or postoperative, or both, may be proved effective in preventing recurrence, especially for lesions below the peritoneal reflection, which is the most frequent site of recurrent disease. Finally, ultraradical pelvic surgery has reached its anatomical and pathologic limit. It only remains for the mortality and survival results to be further improved by continued refinements in the technicalities of the operation and in the judgment and selection of patients for it. Multimodal adjunctive therapy has an emerging role, as does selection of patients for functional preservation and reconstruction. The procedures should continue to be done in institutions where special studies are being conducted and where trained and experienced personnel are available with the necessary ancillary services.

Carcinoma of the anal region.

Preservation of anorectal function makes chemoradiotherapy attractive as the primary treatment in patients with squamous cell carcinoma of the anal region. Despite variations in techniques of chemoradiotherapy administration, the accumulated experience of a number of institutions indicates substantial improvement over previous approaches, which included surgery or radiation therapy individually. Although no longer providing the definitive therapeutic role in this disease, the surgeon is frequently asked to evaluate lesions suspected of being anal malignancies. In addition, it is the surgeon who most often performs the diagnostic biopsy, consults on local complications of chemoradiotherapy, and manages complications of local recurrence. In this context, optimal care includes early organization of the medical oncologist, radiation therapist, and surgeon to participate in the initial diagnostic evaluations, examinations with the patient under anesthesia, and follow-up during therapy. A complete response is often not evident until 2 to 3 months after treatment. We recommend a follow-up schedule of monthly visits for the first 6 months, examinations every 3 months for the next 2 years, and assessment every 6 months thereafter. Evaluation during early routine visits includes manual and proctoscopic examination of the perineum and rectum and review of the hemogram and liver enzyme levels in the serum. CT, MRI, or lower endoscopy procedures are performed only if clinical examination or studies suggest the possibility of recurrence or a second primary tumor. Patients with an incomplete response to therapy after 3 months often undergo examination under anesthesia with biopsy of suspect areas. Chronic inflammatory changes in the area of previous carcinoma may be interpreted as persistent disease. Thus histologic proof of recurrent malignancy must be obtained before considering surgical or chemoradiotherapy salvage treatment.