Surgical resection is necessary to maximize tumor control in function-preserving, aggressive chemoradiation protocols for advanced squamous cancer of the head and neck (stage III and IV).

BACKGROUND: The role of surgery in aggressive chemoradiation protocols for advanced head and neck cancer has been questioned because of the quoted high clinical response rates in many series. METHODS: The role of surgical resection was examined in an aggressive neoadjuvant protocol of weekly paclitaxel, carboplatin, and radiation for stage III and IV with completion of radiation to 72 Gy if biopsy at the primary site was negative after administration of 45 Gy. Of 43 patients enrolled, 38 completed the protocol. The clinical response was 100% (including 18 complete and 20 partial responses). RESULTS: The complete pathologic response (negative primary site biopsy at 45 Gy) was 25 of 38 (66%). Of patients who presented with N1 to N3 nodes, neck dissection revealed residual nodal metastases in 22%. Surgical resection of the primary site was required in 13 patients, including 5 with larynx cancer and 2 with base of tongue cancers. Four patients had resection with reconstruction for advanced mandible floor of mouth cancer, and one had resection of nasal-maxillary cancer. Functional resection was performed in 9 of 12 patients. The median progression free and overall survival was 64% and 68%, respectively, at median follow-up of 50 months. Nine patients developed recurrence (three local and six distant). There were no failures in the neck. Salvage surgery was performed in one patient with local and one with distant disease. CONCLUSIONS: Surgical resection is an essential component of aggressive chemoradiation protocols to ensure tumor control at the primary site and in the neck.

Preoperative chemotherapy, radiotherapy, and surgical resection of locally advanced pancreatic cancer.

HYPOTHESIS: Neoadjuvant therapy has the potential to induce regression of high-risk, locally advanced cancers and render them resectable. Preoperative chemoradiotherapy is proposed as a testable treatment concept for locally advanced pancreatic cancer. DESIGN: Fourteen patients (8 men, 6 women) with locally advanced pancreatic cancer were surgically explored to exclude distant spread of disease, to perform bypass of biliary and/or gastric obstruction, and to provide a jejunostomy feeding tube for long-term nutritional support. A course of chemotherapy with fluorouracil and cisplatin plus radiotherapy was then initiated. Reexploration and resection were planned subsequent to neoadjuvant therapy. MAIN OUTCOME MEASURES: Tumor regression and survival. INTERVENTIONS: Surgically staged patients with locally advanced pancreatic cancer were treated by preoperative chemotherapy with bolus fluorouracil, 400 mg/m2, on days 1 through 3 and 28 through 30 accompanied by a 3-day infusion of cisplatin, 25 mg m2, on days 1 through 3 and 28 through 30 and concurrent radiotherapy, 45 Gy. Enteral nutritional support was maintained via jejunostomy tube. RESULTS: Of 14 patients who enrolled in the protocol and were initially surgically explored, 3 refused the second operation and 11 were reexplored; 2 showed progressive disease and were unresectable and 9 (81%) had definitive resection. Surgical pathologic stages of the resected patients were: Ib (2 patients), II (2 patients), and III (5 patients). Pancreatic resection included standard Whipple resection in 1 patient, resection of body and neck in 1 patient, and extended resection in 6 patients (portal vein resection in 6, arterial resection in 4). One patient who was considered too frail for resection had core biopsies of the pancreatic head, node dissection, and an interstitial implant of the tumorous head. Pathologic response: 2 patients had apparent complete pathologic response; 1 patient had no residual cancer in the pancreatectomy specimen, the other patient who had an iridium 192 interstitial implant had normal core biopsies of the pancreatic head. Five patients had minimal residual cancer in the resected pancreas or microscopic foci only with extensive fibrosis, and 2 patients had fully viable residual cancer. Lymph node downstaging occurred in 2 of 4 patients who had positive peripancreatic nodes at the initial surgical staging. There was 1 postoperative death at 10 days. Sepsis, prolonged ileus, and failure to thrive were major complications. In the definitive surgery group the median survival was 19 months after beginning chemoradiotherapy and 16 months after definitive surgery. The absolute 5-year survival was 11% of 9 patients, 1 is surviving 96 months (with no evidence of disease) after chemoradiotherapy and extended pancreatic resection including resection of the superior mesenteric artery and the portal vein for stage III cancer. In the nonresected group the mean survival was 9 months (survival range, 7-12 months) after initiation of chemoradiotherapy. CONCLUSION: A pilot study of preoperative chemoradiotherapy with infusional cisplatin and radiation induced a high rate of clinical pathologic response in patients with locally advanced pancreatic cancer and merits further study in these high-risk patients.

Pelvic resection of recurrent rectal cancer: technical considerations and outcomes.

PURPOSE: Pelvic recurrence of rectal cancer is an ominous event for the patient and a formidable challenge to the managing surgeon. We reviewed the results of abdominosacral resection to manage these patients and correlated outcome (survival and recurrence) with known prognostic factors. METHODS: An abdominosacral resection was performed on 61 patients with pelvic recurrence (53 with curative intent and 6 for palliation; 2 had extended pelvic resection). Of the 53 patients (32 males; average age, 59 years) previous resection included abdominoperineal resection in 27 patients, abdominoperineal resection plus hepatic lobectomy in 2 patients, low anterior resection in 19 patients, plus trisegmentectomy in 1 patient, and advanced primary cancers in 4 patients. Initial primary stage was Dukes B (64 percent) and Dukes C (36 percent). All had been irradiated (3,000-6,500 in 50 patients, 8,300 and 11,000 in 2 patients, and unknown dose in 3 patients). Preoperative carcinoembryonic antigen was elevated (>5 ng/ml) in 54 percent. Extent of resection: high sacral resection S-1-S2 was done in 32 patients, midsacrum in 14 patients, and low S-4-S-5 in 6 patients. Twenty-eight patients (60 percent) required partial or complete bladder resection with or without adjacent viscera, and all had internal iliac and obturator node dissection. RESULTS: There were four postoperative (within 60 days) deaths, 8 percent in curative groups (5.4 percent overall). Major complications included prolonged intubation (20 percent), sepsis (34 percent), posterior wound infection or flap separation (38 percent). The survival rate in the curative group (49 postoperative survivors) was 31 percent at five years, with 13 patients surviving beyond five years. Seven of these patients survived from 5 to 21 years, whereas six patients recurred again and died within 5.5 to 7.5 years after abdominosacral resection. Disease-free survival rate at five years was 23 percent. Recent reconstruction with large composite myocutaneous gluteal flaps in 5 patients permitted complete sacral wound coverage, resulting in earlier ambulation and reduced hospital stay. CONCLUSIONS: Abdominosacral resection permits removal of pelvic recurrence of rectal cancer that is fixed to the sacrum and is associated with long-term survival in 31 percent of patients. Recent technical advances have improved the short-term outcome and have made the procedure more feasible for surgical teams familiar with these techniques.

Preoperative paclitaxel, carboplatin, and radiation therapy in advanced head and neck cancer (stage III and IV).

Preoperative chemotherapy and chemoradiation protocols are generally associated with high clinical response rates but limited pathologic responses for large primary tumors. We have initiated a prospective phase II study of weekly paclitaxel and carboplatin plus concurrent, fractionated external-beam radiation, followed by organ-preserving or function-restorative surgery (when applicable to maximize locoregional tumor control). Operable patients staged by triple endoscopy received a percutaneous gastrostomy and vigorous dental and nutritional support during therapy. Paclitaxel 60 mg/m2 and carboplatin at an area under the concentration-time curve of 1 were administered weekly with radiation therapy 45 Gy, with repeat biopsy of the primary site at 5 weeks. Patients with a positive biopsy had definitive surgery within 4 to 5 weeks. Patients with a negative biopsy received 3 additional weeks of radiation therapy, to a total dose of 72 Gy plus paclitaxel and carboplatin. Forty-three patients were enrolled, including 33 men and 10 women ranging in age from 37 to 81 years. Fourteen patients had stage III disease, 19 patients had stage IVA disease, and 10 patients had stage IVB disease. Sites of disease included the floor of the mouth (n = 8), tongue (n = 8), oropharynx (n = 5), hypopharynx (n = 4), larynx (n = 12), palate-tonsil (n = 2), unknown primary (n = 3), and nasal cavity (n = 1). Of 38 patients evaluable for primary response (two patients had unknown primary tumor, two patients failed to complete the chemoradiation protocol, and one patient was evaluable for toxicity only), 18 patients had a complete clinical response and 20 patients had a partial response; the overall clinical response rate was 100%. A pathologic clinical response at the primary site occurred in 25 of these 38 patients (66%), who subsequently received completion radiation (67 to 72 Gy). After induction chemoradiation, 36 patients with N1-N3 nodes had neck dissection; seven had positive nodes (19%). Fourteen patients had residual cancer at the primary site at the time of the repeat biopsy. Sites of the lesions were the floor of the mouth/mandible (n = 4), nasal cavity/maxilla (n = 2), base of tongue (n = 2), and larynx (n = 6). All were resected with function-preserving reconstruction (two patients required total laryngectomy and one patient refused surgery). At a median follow-up of more than 16 months, progression-free and overall survival rates were 64% and 68%, respectively. Preoperative paclitaxel, carboplatin, and radiation was associated with a high clinical response rate at the primary site and a high level of organ preservation or functional restoration, if ablation was performed.

Preoperative chemoradiation coupled with aggressive resection as needed ensures near total control in advanced head and neck cancer.

BACKGROUND: Preoperative chemotherapy or chemoradiation protocols are generally associated with high clinical response rates, but limited pathologic responses for large primary tumors. We have initiated a prospective phase II study of weekly paclitaxel 60 mg/M2, and carboplatin (AUC of 1) plus concurrent fractionated external beam radiation (45 Gy) followed by organ-preserving (or function restorative) surgery when applicable to maximize local-regional tumor control. PATIENTS AND METHODS: Operable patients staged by triple endoscopy received a percutaneous endoscopic gastrostomy and vigorous dental and nutritional support during therapy. Weekly paclitaxel 60 mg/M2, carboplatin (AUC of 1), and radiation 45 Gy were given with rebiopsy of the primary site at 5 weeks. Patients with positive biopsy had definitive surgery in 4 to 5 weeks. Patients with negative biopsy-results received 3 additional weeks of radiation, to a total dose of 72 Gy plus carboplatin and paclitaxel. RESULTS: The 35 patients were 29 men and 6 women, aged 40 to 71 years, with stage III (12) or stage IV (23) cancer. The site of the cancer was oral cavity, 10; base of tongue, 3; oropharynx, 3; hypopharynx, 4; larynx, 12 (glottic, 6; supraglottic, 6), unknown primary, 2; other, nasal cavity, 1. Of 34 evaluable patients, 16 (47%) had a complete clinical response (CR) and 18 (53%) had a partial response (PR); total clinical response rate was 100%. A pathologic CR at the primary site occurred in 23 of 34 patients (68%; 2 had an unknown primary) who went on to completion radiation at 67 to 72 Gy. After induction chemoradiation 21 patients with N1-3 nodes had neck dissection; 6 (31%) had positive nodes. Twelve patients had residual cancer at the primary site at time of rebiopsy: mandible, 4; maxilla, 1; base of tongue, 2; larynx, 4; floor of mouth, 1; and nasal cavity, 1. All were resected with function-preserving reconstruction. At median follow-up of >12 months, progression-free and overall survivals were 71% and 83%, respectively. CONCLUSION: Preoperative treatment with paclitaxel, carboplatin, and radiation is associated with high CR at the primary site and a high level of organ preservation or functional restoration if ablation is done.

Recurrence patterns with concurrent platinum-based chemotherapy and accelerated hyperfractionated radiotherapy in stage III and IV head and neck cancer patients.

BACKGROUND: Stage III and IV squamous cell cancers of the head and neck are often unresectable at presentation and are associated with poor disease-free and overall survival rates. A phase II study using concurrent cisplatin and radiotherapy in advanced head and neck cancer indicated impressive local-regional control and survival with organ preservation. METHODS: A multicentered phase II study was undertaken consisting of 1.8 Gy fraction radiotherapy for 2 weeks followed by 1.2 Gy BID hyperfractionation to 46.8 Gy. Continuous infusion cisplatin 20 mg/m2 was given on days 1 through 4 and 22 through 25. Biopsy of the primary tumor was done at this point, and patients with clinical and pathologic complete response continued with hyperfractionated radiotherapy to 75.6 Gy plus simultaneous carboplatin 25 mg/m2 BID for 12 consecutive days. Residual disease at 46.8 Gy required curative surgery. RESULTS: Seventy-four patients entered the study, and 73 completed their treatment. Twenty were stage III and 54 were stage IV. Fifty patients had involved regional lymph nodes. Treatment was well tolerated with only one grade IV hematologic toxicity. At 46.8 Gy, biopsy revealed a complete response in 75% of the primary sites and 47% of the nodes. Only 12 patients required resection of the primary lesion. At 4 years (median follow-up is 26 months), 29 patients have recurred. CONCLUSIONS: Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in stage III and IV head and neck cancer yields excellent local-regional control with organ preservation. This protocol is intensive, and some patients have distant failures.

Concurrent paclitaxel, carboplatin, and radiotherapy in advanced head and neck cancers: a phase II study--preliminary results.

Radiotherapy or surgery alone for advanced head and neck cancer generally yields poor results. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin have both shown excellent radiosensitization through two discrete mechanisms, namely, blocking the cell cycle in the G2/M phase and inhibiting DNA repair. In an effort to improve locoregional control and survival, a prospective phase II study was initiated using paclitaxel 60 mg/ml and carboplatin (area under the concentration-time curve of 1), each given as a single dose weekly with concurrent conventional fractionated external beam radiotherapy. Patients were stratified into two groups: operable and inoperable/unresectable. The operable and inoperable groups received 5 weeks (45 Gy) and 8 weeks (72 Gy) of chemoradiotherapy, respectively. Patients in the operable group were evaluated with repeat biopsies from the primary site after 5 weeks. Those with a positive biopsy underwent surgery; those with a negative biopsy received 3 additional weeks of chemoradiotherapy. Thirty-four patients were entered in the operable group (28 men and six women; 40 to 71 years of age; 12 stage III and 22 stage IV). Of 26 evaluable patients, 19 (73%) had a complete clinical response (95% confidence interval [CI], 52% to 88%) and six (23%) had a partial response (95% CI, 9% to 44%), for a total clinical response rate of 96% (95% CI, 80% to 100%). A pathologic complete response at the primary site (two had an unknown primary site) occurred in 17 of 24 (71%) patients (95% CI, 49% to 87%). Of 20 patients with N1-3 nodes who underwent neck dissection, 17 (85%) had pathologically negative lymph nodes. Seven patients with residual tumor at the primary site were resected (oral cavity, three; maxilla, one; base of tongue, one; and larynx, two). Grades 3 and 4 mucositis were seen in 19 (73%) patients; mucositis was the most common and significant morbidity. Accrual for the inoperable group continues. Concomitant paclitaxel, carboplatin, and external beam radiotherapy yielded excellent clinical responses, but produced significant grade 3/4 toxicity. In the operable group, the majority of responders had a complete pathologic response. These preliminary findings will be assessed in terms of response duration, organ preservation, and long-term survival.

Synchronous colon carcinomas: molecular-genetic evidence for multicentricity.

BACKGROUND: The synchronous presentation of multiple colonic adenocarcinomas is an unusual, but well-recognized event accounting for approximately 2-11% of these neoplasms. Synchronous tumors may have a different biology and prognosis than solitary tumors. Evidence based on measurement of DNA ploidy suggests that a significant percentage of synchronous tumors have a common clonal origin, probably resulting from translumenal metastasis. METHODS: Fifteen synchronous colorectal cancers (30 tumors) were examined for histologic differences as well as genetic mutations. p53 gene abnormalities were detected by polymerase chain reaction (PCR) followed by single-strand conformation polymorphism analysis. Ki-ras mutations were detected by PCR followed by oligonucleotide-specific hybridization. RESULTS: p53 gene mutations were detected in 12 of 30 tumors. In only one case was the same p53 mutation present in both tumors from one patient. Similarly, Ki-ras mutations were observed in 9 of 30 tumors. Concordant Ki-ras mutations were observed in only one case, which was also concordant for p53 mutation. CONCLUSION: Because p53 and Ki-ras mutations tend to occur fairly early in tumor development, it seems likely that cases discordant for p53 and Ki-ras mutations represent independently developing tumor foci. Taken together, these findings strongly suggest that the great majority of synchronous colonic adenocarcinomas arise as independent neoplasms and their worsened prognosis is not a result of unusually early metastatic spread.

Preoperative cisplatin and accelerated hyperfractionated radiation induces high tumor response and control rates in patients with advanced head and neck cancer.

BACKGROUND: Preoperative therapy with concurrent cisplatin infusion and accelerated hyperfractionated radiation has the potential to eradicate pools of resistant cells with high-growth fraction that accumulate during standard radiation therapy. Based on preliminary data showing a high complete response rate (necessary for organ preservation) in patients with advanced squamous cell cancer of the head and neck (stages III and IV), we conducted a multi-institutional study using accelerated hyperfractionated radiation to maximize local and regional tumor control without adding toxicity. PATIENTS AND METHODS: Preoperative radiation was given in 1.8 Gy fractions for 2 weeks followed by 1.2 Gy BID hyperfractionation to 46.7 Gy. Continuous infusion of cisplatin 20 mg/m2 was given on days 1 through 4 and 22 through 25. Patients were initially assessed with panendoscopy and were subsequently reassessed with biopsy of primary site (+/- nodes). Patients with negative primary site biopsy received additional hyperfractionated radiation to 76 Gy with simultaneous carboplatin 25 mg/m2 BID for 12 consecutive days. Patients with residual disease after 47 Gy had resection of primary site and node dissection. Of 69 patients treated, 56 were T3 and T4, and 46 were N1, N2, and N3; 17 patients (25%) were stage III and 50 (72%) were stage IV; in 2 patients (3%) the stage was unknown. RESULTS: Treatment was well tolerated with no grade IV toxicities, but there were 13 patients with grade III toxicities (mucositis, dysphagia, or hematological toxicity). Biopsy specimens were taken from 84% of the patients, and 81% of the primary sites showed pathologic complete response and 49% of the lymph nodes showed a pathologic complete response. Thirty-four patients underwent curative surgery. Eleven required resection of the primary and 23 required neck dissection only. At 2 years (median followup 12 months), 44 of 69 patients (64%) have no evidence of disease, 9 are dead of disease, 9 are dead of other causes, and 6 are alive with disease. Surgical toxicities were minimal and primarily limited to fibrosis in 12 patients, edema in 8 patients, tracheoesophageal fistula in 1 patient, and delayed wound healing in 1 patient. Late toxicities included xerostomia in 22 patients, dysphagia in 17, and speech impairment in 9. CONCLUSIONS: Preoperative concurrent radiotherapy and chemotherapy provides a high level of organ preservation and local and regional control because of the high complete response rate at the primary site. A planned neck dissection with minimal morbidity ensures local/regional control, as well as providing definitive staging information. A randomized evaluation is suggested for this program.

Pelvic resection of recurrent rectal cancer.

OBJECTIVE: The authors describe their experience with pelvic resection of recurrent rectal cancer with emphasis on patient selection for curative intent based on known tumor risk factors. SUMMARY BACKGROUND DATA: Pelvic recurrence is a formidable problem in 30% of patients who have undergone a curative resection of primary rectal cancer. Although radiation can reduce the development of local recurrence and can provide palliation to many patients with localized disease, it is not curative. The authors and others have used the technique of abdominal sacral resection (ABSR) with or without pelvic exenteration to resect pelvic recurrence and its musculoskeletal extensions in selected patients with satisfactory long-term survival. METHODS: The technique of ABSR with or without pelvic exenteration or resection of pelvic viscera, which the authors have described previously, was used in 53 patients with recurrent rectal cancer--47 patients for curative intent and 6 for palliation. Previous surgeries were abdominal perineal resections (APRs) in 26 patients, anterior resections in 19 patients, and other procedures in 2 patients; original primary Dukes' stage was B in 52% and C in 48%. Almost all patients had been irradiated previously, generally in the 4000 to 5900 cGy range. Preoperative carcinoembryonic antigen (CEA) levels (before ABSR) were elevated (> 5 ng/mL) in 54%. RESULTS: Postoperative morbidity was encountered in most patients. Mortality was 8.5% in the curative group. Long-term survival for 4 years was achieved in 14 of 43 patients (33%), and 10 patients were alive with an acceptable quality of life after 5 years. Patients who had previous anterior resections or whose preoperative CEA levels were less than 10 ng/mL had a survival rate of approximately 45%, whereas patients with previous APRs and preoperative CEA levels greater than 10 ng/mL had a survival rate of only 15% to 18%. Patients with bone marrow invasion, positive margins, or pelvic node metastases had a median survival of only 10 months. CONCLUSIONS: Pelvic recurrence of rectal cancer can be resected safely with expectation of long-term survival of 33%. Patient selection based on known risk factors can identify patients most likely to benefit from resection and eliminate those who should be treated for palliation only.

Composite resection of posterior pelvic malignancy.

Advanced pelvic cancer is a formidable challenge to surgical resection. These tumors commonly invade the bony pelvis, may involve other viscera, and usually have been irradiated previously. The authors are presenting experience with 76 patients who had composite resection of posterior or lateral pelvic malignancy. Fifty-eight patients had secondary cancers involving the musculoskeletal pelvis. This included 47 patients with advanced carcinoma of the rectum (41 curative, 6 palliative), 10 epidermoid cancers of the anorectum (8) or cervix (2), and 1 bladder cancer. Among the 18 patients with primary pelvic tumors were three patients with chordomas, six with bone tumors (osteosarcoma chondrosarcoma, grade III giant cell tumor), and nine with soft tissue tumors. All required major resection of the sacrum or pelvic side walls, and one half had an additional exenterative procedure. The overall mortality rate was 7.9%. Long-term estimated survival was 24% in patients having curative resection of recurrent rectal cancer, and 22.5% in 10 patients with advanced epidermoid cancer. Fifty per cent of patients with primary bone or soft tissue tumors survived from 13 to 88 months. Most patients had reasonable return of function, and were able to return to work or resume their normal previous lifestyle.

Head and neck sarcoma: report of the Head and Neck Sarcoma Registry. Society of Head and Neck Surgeons Committee on Research.

A Head and Neck Sarcoma Registry was established by the Society of Head and Neck Surgeons to review treatment results of a rare tumor by surgeons with special interest in this anatomic site. Two hundred fourteen patients were analyzed. There were 194 adult tumors and 20 pediatric tumors. The major sites included parotid and neck, 20%; face and forehead, 18%; maxilla and palate, 13%; scalp, 12%; mandible, 11%; paranasal sinuses, 7%; larynx, 2%; and oral cavity, 5%. Eighty-four percent were resectable. The disease-free survival was 56%; overall survival was 70% at 5 years. Major determinants of survival were adequacy of resection (margins free of tumor) and tumor type. Survival differed according to tumor cell type (tumor grade was not available). Patients with chondrosarcoma and dermatofibrosarcoma had survival approaching 100%. Patients with malignant fibrous histiocytoma (MFH) and fibrosarcoma (FSA) had intermediate survival of 60% to 70%. The worst survival, less than 50% at 5 years, occurred in patients with osteosarcoma, angiosarcoma, and rhabdomyosarcoma in decreasing order. This suggests a rationale for identifying high-risk patients for prospective adjuvant protocols. This study emphasizes the value of recording uncommon tumors to provide relevant information for future study and possibly therapy.

Perforated peptic ulcer. Determinants of morbidity and mortality.

A review of 109 patients with perforated peptic ulcer revealed a sex ratio of 60:49, male:female, with mean age of 67 (76 patients greater than or equal to age 50). Peritoneal cultures were positive in 52 per cent, with the most common organisms streptococci and fungi. Subsequent infectious morbidity with these organisms was rare. Postoperative respiratory and renal failure were associated with intraoperative hypotension (systolic pressure less than 90 mm Hg). Mortality was associated with age greater than 55 and intraoperative hypotension. We conclude that in the 1980s perforated peptic ulcer occurs most frequently in older patients and that acid stomach contents does not ensure sterility, yet subsequent infectious morbidity is rare. Intraoperative hypotension, which occurs especially in patients greater than 55 years, results in significant morbidity and mortality. Attention to preoperative and intraoperative resuscitation is the single most effective therapy for reducing morbidity and mortality from this disease.