Induction cetuximab, paclitaxel, and carboplatin followed by chemoradiation with cetuximab, paclitaxel, and carboplatin for stage III/IV head and neck squamous cancer: a phase II ECOG-ACRIN trial (E2303).

BACKGROUND: E2303 evaluated cetuximab, paclitaxel, and carboplatin used as induction therapy and concomitant with radiation therapy in patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) determining pathologic complete response (CR), event-free survival (EFS), and toxicity. PATIENTS AND METHODS: Patients with resectable stage III/IV HNSCC underwent induction therapy with planned primary site restaging biopsies (at week 8 in clinical complete responders and at week 14 if disease persisted). Chemoradiation (CRT) began week 9. If week 14 biopsy was negative, patients completed CRT (68-72 Gy); otherwise, resection was carried out. p16 protein expression status was correlated with response/survival. RESULTS: Seventy-four patients were enrolled; 63 were eligible. Forty-four (70%) were free of surgery to the primary site, progression, and death 1-year post-treatment. Following induction, 41 (23 CR) underwent week 8 primary site biopsy and 24 (59%) had no tumor (pathologic CR). Week 14 biopsy during chemoradiation (50 Gy) in 34 (15 previously positive biopsy; 19 no prior biopsy) was negative in 33. Thus 90% of eligible patients completed CRT. Overall survival and EFS were 78% and 55% at 3 years, respectively. Disease progression in 23 patients (37%) was local only in 10 (16%), regional in 5 (8%), local and regional in 2 (3%), and distant in 5 patients (8%). There were no treatment-related deaths. Toxicity was primarily hematologic or radiation-related. p16 AQUA score was not associated with response/survival. CONCLUSIONS: Induction cetuximab, paclitaxel, and carboplatin followed by the same drug CRT is safe and induces high primary site response and promising survival. CLINICAL TRIALS NUMBER: NCT 00089297.

Paraproteinemia and reticulum cell sarcoma in an inbred mouse strain.

Mice of the inbred SJL/J strain have a high incidence of a proliferative disease affecting several cell types, including reticulum cells and plasma cells, which is frequently accompanied by gamma(1) and gamma(2) paraproteinemia. In only some instances can seriallytransplantable lines of neoplastic cells be obtained; these are reticulum cell sarcomas. Mice with transplanted reticulum cell e arcomas do not have paraproteinemia and may develop profound hypogammaglobulinemia. The disease may be viewed as an abnormal proliferation of reticulum cells which differentiate into plasma cells with consequent paraproteinemia; the subsequent emergence of transplantable reticulum cell sarcoma appears as an end stage in which this capacity to differentiate is lost.

Antitumor effects of a normal human serum factor (normal human globulin fraction 1) on human tumor cells in vitro.

Normal human globulin fraction 1 (NHG-1) produced cytotoxicity and/or cytostasis as well as inhibition of protein synthesis in 8 well-characterized human tumor cell lines (4 breast cancer, 1 colon cancer, 1 melanoma, and 2 leukemia) and in 2 variants of murine B-16 melanoma. NHG-1 was not cytotoxic for the Chang liver cell line, a normal kidney embryo line, or for normal lymphocytes or macrophages when used in lower concentrations but was growth inhibitory for normal cells in higher concentrations. Although lymphocyte blastogenesis with phytohemagglutinin (PHA) was inhibited by high concentrations of NHG-1, augmentation of the lymphocyte PHA response was seen at lower concentrations, suggesting a lymphokine-like effect. Preincubation with the mitogen partially nullified these NHG-1 effects (suggesting the need for cell surface binding). Although NHG-1 antitumor activity was confirmed in selected human and murine tumor cell lines, the mechanism of its activity is unknown. Occurrence of NHG-1 in the alpha 2-globulin region (an area rich in immune-regulating factors) suggests that NHG-1 may have general "cytokine"-like effects and may be capable of regulating replication of both normal and transformed cells.

Leukocyte migration inhibition among breast cancer patients in response to various oncogenic viruses.

The direct leukocyte migration inhibition (LMI) test was done with leukocytes from healthy women and from patients with primary operable breast cancer, benign breast disease, or head and neck cancer. Purified preparations of murine mammary tumor virus (MuMTV), Mason-Pfizer monkey virus (MPMV), and murine leukemia virus (MuLV) were used. For each virus, the lowest 10th percentile of the LMI responses of controls was used to discriminate positive from negative responses. Leukocytes from 46 of 94 (49%) breast cancer patients responded to MuMTV, which was significantly different from each of the other test groups: Positive reactions were observed in only 9 of 67 (13%) healthy persons, 2 of 32 (6%) patients with benign breast tumors, and 2 of 20 (10%) patients with head and neck cancer. Although leukocytes from 29% of the breast cancer patients responded to MPMV, this response did not significantly differ from that observed in healthy women (14%), in patients with benign disease (20%), or in patients with head and neck cancer (20%). The leukocytes from the breast cancer patients were not reactive to MuLV. LMI tests to both MuMTV and extracts of MCF-7 cultured breast cancer cells were done in 36 breast cancer patients and 40 healthy women simultaneously. Of the breast cancer patients, 75% responded to MuMTV and/or MCF-7 antigen as compared to 18% of the controls (P less than 0.005). These data suggest that leukocytes from breast cancer patients are presensitized to MuMTV and antigen(s) present in MCF-7 breast cancer cell line, but not to MPMV or MuLV.

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity and spontaneous cytotoxicity in normals and cancer patients as assayed by human erythrocyte lysis.

The monocyte-macrophage system has long been recognized as a necessary accessory to the immune response. Recently, however, monocyte-macrophages have been shown to be important effectors of cell-mediated cellular cytotoxicity (both antibody dependent and antibody independent). In this study, monocyte-mediated cellular cytotoxicity of both types was assessed on 51Cr-labeled human erythrocytes (type B+) using autologous and standardized AB serum, and monocytes from 57 normal controls, 16 women with benign breast disease, and 175 patients with cancers of the breast (44 patients), colorectum (46 patients), head and neck (33 patients), lung (13 patients), and melanoma (39 patients). Although results were variable, many of the patients had depressed antibody-dependent cellular cytotoxicity suggesting decreased ability of their monocyte-macrophage to lyse the sensitized erythrocytes. Enhanced antibody-dependent cellular cytotoxicity was observed in patients with localized colorectal cancer, but this effect was reversed in patients with advanced disease. Serum factors did not significantly affect responses in most cases. The clinical relevance of this assay remains to be determined.

Transient stimulation of the c-Jun-NH2-terminal kinase/activator protein 1 pathway and inhibition of extracellular signal-regulated kinase are early effects in paclitaxel-mediated apoptosis in human B lymphoblasts.

We demonstrate here that paclitaxel exposure to RPMI-1788 B lymphoblasts caused a dose- and time-dependent increase in nuclear factor activator protein 1 (AP-1) DNA binding activity. The basal DNA binding activities of nuclear factors NF-kappaB and Ets were not affected by paclitaxel. Consistent with these biochemical events, paclitaxel stimulated AP-1-dependent chloramphenicol acetyltransferase (CAT) reporter gene transcription in vivo, as directed from a tetradecanoyl phorbol acetate-inducible promoter. AP-1 binding activity of nuclear extracts isolated from paclitaxel treated cells was reduced following immunodepletion with antibodies directed against individual Jun family proteins, whereas anti-cFos, anti-Fra1, and anti-FosB antibodies were not inhibitory. Paclitaxel caused a rapid and transient increase in c-Jun NH2-terminal kinase (JNK) activity, a proposed mediator of stress activation pathways. By contrast, exposure to paclitaxel produced a transient reduction in the extracellular signal-regulated mitogen-activated protein kinase 2 (ERK2) activity, a proposed mediator of growth factor-stimulated proliferation pathways. Transient activation of the c-Jun-NH2-terminal kinase/AP-1 pathway, together with down-regulation of ERK2 activity, may be a key event in the early response of RPMI-1788 B lymphoblasts to paclitaxel exposure.

Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study.

In 1980, a consensus chemotherapy intergroup study for advanced malignant mesothelioma was initiated based on a collaborative agreement among the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), and the Southeastern Cancer Study Group (SECSG). The purpose of the study was to evaluate cyclophosphamide (500 mg/m2 day 1), imidazole carboxamide (250 mg/m2 days 1 through 5), and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (50 mg/m2 day 1) v cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) in a randomized prospective clinical trial involving 76 fully evaluable patients with advanced stages II to IV malignant mesothelioma. A total of nine responses (12%) were documented, including three complete and six partial responses. There was no significant difference in response duration or survival between treatment arms. Leukopenia (greater than 2,000/microL) was observed in 46% of patients treated with the three-drug combination and 38% of patients receiving the two-drug combination. The variables of performance status 0-1 and the absence of prior chemotherapy/radiotherapy were significant with respect to favorable impact on survival. We conclude, based on the minimal benefit observed, that the combination of cyclophosphamide and doxorubicin with or without imidazole carboxamide does not warrant further investigation in patients with advanced-stage malignant mesothelioma.

Paclitaxel and concurrent radiation for locally advanced pancreatic and gastric cancer: a phase I study.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and potential antitumor activity of weekly paclitaxel with concurrent radiation (RT) for locally advanced pancreatic and gastric cancer. PATIENTS AND METHODS: Thirty-four patients with locally advanced adenocarcinoma of the pancreas or stomach were studied. The initial dose of paclitaxel was 30 mg/m2 by 3-hour intravenous (I.V.) infusion repeated every week for 6 weeks with 50 Gy RT. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients until dose-limiting toxicity was observed. RESULTS: The dose-limiting toxicities at 60 mg/m2/wk were abdominal pain within the RT field, nausea, and anorexia. Of 23 patients with assessable disease, 11 (seven with gastric, four with pancreatic cancer) had objective responses for an overall response rate of 48%. CONCLUSION: Concurrent paclitaxel with upper abdominal RT is well tolerated at dosages that have substantial activity. A phase II trial of neoadjuvant paclitaxel and RT at the MTD of 50 mg/m2/wk is underway.

Changing gastric cancer treatment in the United States and the pursuit of quality.

The low incidence of gastric cancer in the US presents various quality challenges. For most US practitioners, individual experience is inadequate. Accrual to clinical trials testing new treatments can be daunting. However, through the use of nationally available clinical trials sponsored by many trial groups working in concert, and the use of national registries for treatment and outcome surveillance, a path to increased gastric cancer survival has been charted. Moreover, systems for continuous quality improvement at the institutional level are in place. Quality assurance is an increasing concern of both private and governmental groups. In this article, we summarize recent national US clinical trial findings concerning gastric cancer treatment, highlight national assessment systems for cancer outcomes, and describe what these systems tell us about the current status of gastric cancer care in the US, highlighting challenges and areas for potential improvement.

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.

Immunotherapy of mice with an irradiated melanoma vaccine coupled with interleukin-12.

Interleukin (IL)-12 can activate cytotoxic lymphocytes, stimulate natural killer cell activity, induce the production of INF-gamma and inhibit the development of various experimental tumors. We previously demonstrated that immunotherapy of melanoma bearing mice with an irradiated melanoma vaccine (IMV) coupled with IL-2 or GM-CSF had beneficial effects against primary melanoma growth and against subsequent spontaneous metastasis. We also had found that treatment of melanoma bearing mice with IL-12 (300 ng/day) for 4 weeks inhibited the development of primary melanoma tumors in 40% of mice. The purpose of this study was to investigate the efficacy of combined therapy of experimental melanoma with an IMV prepared from B16F10 melanoma cells coupled with IL-12 treatment. C57BL/6 mice were challenged subcutaneously in the tail with B16F10 melanoma cells and by the 45th day, more than 50% of the mice had developed visible primary melanoma tumors at the injection site. Subsequent immunotherapy of mice with IMV, when coupled with IL-12, provided partial inhibition of primary melanoma tumor growth. Optimal results against primary tumor growth were observed when IMV therapy was coupled with IL-12 at a dose of 50 ng/day. Combination of IMV with IL-12 at a dose of 100 ng/day significantly reduced melanoma metastasis to the lungs compared with control mice, and an improvement in mean survival time was observed in mice treated with a combination of IMV with IL-12 (300 ng/day).

Surgical therapy of pancreatic cancer.

Surgical resection remains the only curative modality for pancreatic cancer. Improvements in surgical technique have greatly reduced the morbidity and mortality from pancreatic resection. These results clearly justify the use of pancreatic resection for localized and resectable pancreatic cancer. New surgical techniques such as laparoscopy can aid in the proper selection of candidates for curative resection. Integration of surgery with more effective treatments to prevent systemic relapse are needed to further improve survival.

Concurrent platinum-based chemotherapy and hyperfractionated radiotherapy with late intensification in advanced head and neck cancer.

PURPOSE: To determine whether a course of hyperfractionated radiation therapy concomitant with escalated radiosensitizing platinum compounds can be administered with acceptable morbidity and achieve a high rate of loco-regional control for Stage III and IV head and neck cancer and whether the patients can be tumor free at the primary site after initial therapy and cured by the additional chemoradiation without radical resection of the primary tumor. METHODS AND MATERIALS: Patients with Stage III/IV head and neck cancer were treated in this multicenter Phase II Study with 1.8 Gy fraction radiotherapy for 2 weeks, with escalation to 1.2 Gy b.i.d. hyperfractionation to 46.8 Gy. Concomitant continuous infusion cisplantinum (CDDP) 20 mg per meter square on day 1 to 4 and 22 to 25 was given. Reassessment by biopsy of primary and nodes was done. Patients with a complete response continued with hyperfractionated radiotherapy to 75.6 Gy with simultaneous carboplatinum (Carbo), 25 mg per meter square b.i.d. for 12 consecutive treatment days. Patients with residual disease at 46.8 Gy required curative surgery. Seventy-four patients were treated at the three institutions; 20 were Stage III and 54 were Stage IV. All patients had daily mouth care, nutritional, and psychosocial support. RESULTS: This regime was well tolerated. Eighty-five percent of toxicities were Grade 1 or 2 and there was only one Grade 4 hematologic toxicity. Late toxicities included xerostomia in 25 patients, dysphasia in 18, and mild speech impediment in 11. Biopsies of primary site were done after the first course of treatment in 59 patients. Neck dissections were performed in 35 patients. Forty-four of 59 (75%) primary sites and 16 of 35 (46%) lymph nodes had pathologically complete response (CR). Of the 74 patients, only 12 required surgical resection of the primary site. Thirty-five of the 50 node positive patients had neck dissections, 16 of these were CRs at surgery. At 4 years (median follow-up of 26 months), disease-specific survival is 63%. The actuarial survival for all patients is 51%. Patients with pathological CR after initial treatment have disease specific survival of 73% at 4 years vs. 48% of patients with partial response (PR) only. CONCLUSION: This study, developed on the basis of radiobiological and cell kinetic precepts, produced results that compare favorably with other reports of management of patients with advanced head and neck cancer. In comparison with our previous study, these results are comparable, not impressively better. The associated morbidity was somewhat worse.

Paclitaxel and concurrent radiation for gastric cancer.

PURPOSE: To determine the activity and toxicity of paclitaxel and concurrent radiation for gastric cancer. METHODS AND MATERIALS: Twenty-seven patients were studied. Twenty-five had proximal gastric cancers, two had distal cancers. Eight had esophageal extension, 6 had celiac adenopathy, and 7 had retroperitoneal adenopathy. Patients received paclitaxel, 50 mg/m(2) by 3-hour intravenous (IV) infusion, weekly, on days 1, 8, 15, 22, and 29. Radiation was administered concurrently to a total dose of 45.0 Gy, in 1.80 Gy fractions, for 25 treatments. Patients who were medically or surgically inoperable received a sixth week of paclitaxel with a radiation boost to 50.4 Gy. RESULTS: Esophagitis and gastritis were the most important toxicities, Grade 3 in four patients (15%), and Grade 4 in three patients (11%). Five patients (19%) had Grade 3 nausea. The overall response rate was 56%, including three patients (11%) with a complete response. The 2-year progression-free and overall survival rates were 29% and 31%, respectively. CONCLUSION: Concurrent paclitaxel and radiation demonstrates substantial local-regional activity in gastric cancer. Future investigations combining paclitaxel and radiation with other local-regional and systemic treatments are warranted.

A new mouse model of experimental melanoma for vaccine and lymphokine therapy.

The annual incidence of malignant melanoma is estimated at 10-12 per 100,000 inhabitants in countries of central Europe and the United States, and alarmingly there has been a dramatic upward trend in that estimate. The B16 murine melanoma is a rapidly growing metastatic tumor of spontaneous origin, as are human malignant melanomas. Melanoma cells produce specific antigens which are uniquely different from normal cellular antigens, and the expression of such antigens is the cornerstone for preparation of anti-melanoma vaccines. One major problem in evaluating the effectiveness of vaccination and other biologic therapies is the variability of experimental tumor models. A new metastatic model of experimental melanoma which was developed in our laboratory imitates the major clinical stages of malignant metastatic melanoma: stage I, primary (local) tumor growth and bone marrow invasion; stage II, regional lymph node involvement; and stage III, metastasis to distant organs, such as the lungs. This model has been used successfully for screening vaccines constructed in our laboratory. Immunization with formalinized vaccines (of extracellular antigens, intact melanoma cells, or B700 antigen) or irradiated vaccines (of intact melanoma cells) partially inhibit primary melanoma tumor growth, reduce metastasis to regional lymph nodes and lungs, and significantly increase mean survival time. These anti-tumor effects were improved when polyvalent and monovalent vaccines were combined with IL-2 therapy. We also compared the immunogenic activity of vaccines made from B16 melanoma cells transfected with genes encoding murine IL-2 or GM-CSF, and effects on tumor bearing mice were compared with or without therapy using the corresponding lymphokines. In sum, comparison of antibody production, growth of primary melanoma tumors, number of surviving mice, mean survival time, and percent of mice with lung metastases, showed that the best course of immunotherapy involves vaccination of mice with irradiated B16 melanoma cells transfected to secrete GM-CSF, coupled with GM-CSF therapy.

Immune reactivity in primary carcinoma of the lung and its relation to prognosis.

Detailed studies of immune reactivity were performed in 154 patients with primary lung cancer, 20 patients with benign thoracic lesions, and 109 healthy persons. Reactions to the 2,4-dinitrochlorobenzene (DNCB) skin test were postive in 73 per cent of patients with lung cancer and all (100 per cent) of the patients with benign disease (p less than 0.05). The incidence of DNCB reactions was 78 per cent for Stage I and II cancers (37 patinets), 73 per cent for resectable Stage III cancer (22 patients), and 66 per cent in patients with unresectable or inoperable Stage III cancer. DNCB reactivity showed a relationship to primary histology. The incidence of DNCB positive reactions was 80 per cent in patients with epidermold carcinoma versus 57 per cent in patients with adenocarcinoma, 64 per cent in patients with oat cell cancer, and 80 per cent in patients with terminal bronchiolar carcinoma. In vitro immune studeis correlated best with stage of disease. These included the absolute lymphocyte count and absolute T cell count and lymphoxyte stimulation witalen A (Com A). These values were in the normal range in patients with Stage I cancer but were significantly depressed in patients with Stage III cancer. Svrvival curves were plotted in patients with Stage III disease according to the responses to three immune parameters: DNCB, absolute lymphocyte count, and PHS stimulation. Although patients with normal reactions generally had better survival rates, PHA responses showed the most significant correlation to survival. These tests support the usefulness of immune testing as an additional parameter of assessing biological risk in patients with primary lung cancer.

Are carcinoembryonic antigen levels of value in the curative management of colorectal cancer?

Although the carcinoembryonic antigen (CEA) is not specific for colorectal cancer, its strong correlation with many aspects of the disease has made it very useful in clinical management of this malignancy. There is controversy, however, about the real value of CEA determinations in the clinical decision-making process and about their impact on patient prognosis. This review analyzes the relative values of the preoperative CEA and postoperative serial CEA levels, the correlation with different patterns of recurrence, and the potential for detecting early recurrence and selecting patients for second-look surgery. Although there is potential for CEA-directed second-look surgery to retrieve patients through resection of early recurrence and possibly to increase the survival rate, the long-term effects on prognosis are yet to be determined.

The leukocyte migration inhibition response to certain breast cancer-related antigens (MCF-7 and MuMTV): their potential as discriminants.

Certain oncogenic viruses have been implicated in human breast cancer, including the murine mammary tumor virus (MuMTV) and the Mason-Pfizer monkey virus (MPMV). We have used the leukocyte migration inhibition (LMI) response to assay the response to several potential breast cancer-related antigens, including MuMTV, MPMV, and a breast cancer cultured cell line, MCF-7, in 96 breast cancer patients, in 32 women with benign breast disease, and in 67 normal women. The lowest tenth percentile of control (LMI) responses was used as the cutoff point to designate responders. Breast cancer patients showed significant responses to MuMTV (49% and to MCF-7 (50%), but not to MPMV (29%). In a paired-antigen study using MuMTV and MCF-7, 75% of the breast cancer patients responded, versus 18% of the normal women (P less than 0.0050). The potential for this assay to distinguish "normal" from "breast cancer" was analyzed using a migration index derived from discriminant analysis. The ability of the assay to discriminate "normal" from "cancer" was significant (P less than 0.001) and showed a sensitivity of detecting "cancer" of 75%. The overall responses to MuMTV and MCF-7 were analyzed with reference to certain prognostic factors, but showed no relation to age, menstrual status, estrogen receptor status, or stage of disease. The above reactions suggest that a large proportion of breast cancer patients exhibit presensitization to antigenfs found in MuMTV and MCF-7, which may be cross-reactive with antigens in the primary cancer. These responses appear to be independent of major prognostic variables. Further refinement of this assay may yield one which is more highly discriminating for breast cancer.

Current perspectives on repeat hepatic resection for colorectal carcinoma: a review.

BACKGROUND: Recurrence occurs in 65% to 85% of patients after initial hepatectomy for metastases from colorectal cancer. Approximately one half of these have liver metastases, and in 20% to 30% only the liver is involved. Opportunity for resection is frequently limited because of diffuse liver disease or extrahepatic extension, and only 10% to 25% of these patients have conditions amenable to resection. This current review is focused on the rationale, indications, and results of resection of hepatic metastases from colorectal cancer. METHODS: The major series of liver resection were reviewed, and the cases of repeat resections were culled out. In addition to standard clinical parameters, the indications and timing after initial resection and the survival and subsequent recurrence after repeat resection were recorded. RESULTS: A comprehensive review of the 28 series showed that the mean interval between the first and second liver varied from 9 to 33 months and was about 17.5 months in the two largest series. The median survival in series reporting 10 or more patients was 19 months (mean, 24 months), which is comparable to data in single resection series. In the large French Association series containing 1626 patients with single resections and 144 patients with two resections, the 5-year survival was 25% and 16%, respectively. The recurrence rate after repeat resection is high (greater than 60%), and one half are in the liver. The prognostic factors favoring repeat resection are variable, but they include absence of extrahepatic extension of tumor and a complete resection of the liver metastases. CONCLUSIONS: Repeat hepatic liver resection for metastatic colorectal cancer in carefully selected patients appears warranted in view of reasonable survival expectations, which approach that of single liver resection. Risk of recurrence is high, however, suggesting the need for rigorous preoperative and intraoperative assessment and postoperative adjuvant therapy

Preoperative radiation therapy for rectal cancer. An effective therapy in need of a clinical trial.

Sixty patients with locally advanced adenocarcinoma of the rectum have been treated with preoperative high-dose pelvic irradiation in an attempt to improve operability and increase local control. Fifty-six patients showed no evidence of distant metastases at surgery and their records have been analyzed with respect to recurrence patterns, survival, and complications. The results have been compared with those of a similar analysis of 106 patients treated with curative surgery alone. There was a statistically significant improvement in local control between groups, with 16% of patients in the radiotherapy group having a component of local failure compared with 40% in the surgery group. A dose response was observed, with 67% local control at 4000 rad (4000 cGy) and 91% local control at 5000 rad (5000 cGy). Despite the more advanced clinical stage of the irradiated patients, no significant difference in survival was seen between groups, with a five-year survival rate of 52% in the irradiated patients and 48% in patients treated by surgery alone. Preoperative high-dose radiotherapy was well tolerated, with a 5% incidence of major complications in both groups.