Albert B. Einstein

A comparison of cisplatin and the combination of cisplatin and cyclophosphamide in advanced urothelial cancer. A national bladder cancer collaborative group a study

A prospective multi‐institutional randomized trial compared the use of cisplatin (DDP) alone to the combination of DDP and cyclophosphamide in patients with advanced urothelial cancer. Patients were stratified according to measurable or evaluable tumor and performance status. The dose of DDP was 70 mg/m2 and the initial dose of cyclophosphamide was 750 mg/m2. There were ten objective responders (20%), including five complete responders, among the 50 evaluable patients who received DDP alone, and seven responders (11.9%), three complete, among the 59 receiving the combination therapy. Approximately one third of the patients in each treatment arm were stable at the nine‐week evaluation. There was no statistical significance between the response rates in the two treatment arms.

Cisplatin and Full Dose Irradiation for Patients with Invasive Bladder Carcinoma: A Preliminary Report of Tolerance and Local Response

Twenty-seven patients with invasive bladder carcinoma (clinical stages T2 to T4) who were not candidates for cystectomy were treated by transurethral resection, cis-diamminedichloroplatinum (cisplatin) and full dose radiotherapy according to protocol 8 of the National Bladder Cancer Collaborative Group A. Nausea and vomiting occurred in 74 per cent of the patients but were mild in 41 per cent. Maximum followup was 27 months and during that time 3 significant toxic reactions occurred: renal failure, systemic sepsis and a transient partial small bowel obstruction. Of 17 evaluable patients complete responses of the primary bladder cancer to the treatment were achieved in 11 of 13 with stages cT2 and cT3 cancer and in 2 of 4 with stage cT4 disease. The members of National Bladder Cancer Collaborative Group A have found transurethral resection, cisplatin and full dose external beam radiotherapy practical clinically. Longer followup will be necessary to determine if the observed high initial complete response rate of the tumor indicates real lasting benefit for these patients.

MODELS FOR SYNGENEIC ADOPTIVE CHEMOIMMUNOTHERAPY OF MURINE LEUKEMIAS

Adoptive transfer of immunologically competent cells as a form of tumor therapy is based on at least the following assumptions: (a) the tumor possesses tumor-associated or tumor-specific antigens, (b) the critical antitumor reaction responsible for tumor rejection is cell-mediated, ( c ) the host response to tumor is quantitatively or qualitatively defective and therefore permits its progressive growth and, finally, (d) transfer of cells will effectively correct the defect and cure the tumor-bearing host. Unfortunately, our knowledge of the tumor-host relationship is extremely limited-especially with regard to animals bearing hematologic malignancies, i.e., leukemias or lymphomas, in contrast to carcinomas or sarcomas. Moreover, the effector mechanism for tumor rejection is variable among the tumor models and in vitro and in vivo assays employed. Various types of cells such as T cells, B cells, and/or macrophages have been shown to be capable of neutralizing tumor cells in vitro by the Winn assay in vivo, and of protecting mice from a subsequent challenge with syngeneic or allogeneic tumor ce1ls.l. The logical extension of such studies is, of course, to treat an animal bearing a progressively growing syngeneic antigenic tumor with infusions of the putative effector cells, i.e., cells from syngeneic animals immune to tumor antigens. Unfortunately, although such cells administered shortly before or after tumor inoculation can inhibit its growth,3 such immunotherapy has been, with rare exceptions,3* 1 ineffective if instituted once the tumor has become clinically detectable. Thus, immunotherapy provides the advantage of unique antitumor specificity yet is limited by its inability to cope with a large tumor load. This sharply contrasts cytotoxic drugs or irradiation which can destroy a large tumor load but are limited by the relative nonspecificity of their activity. Therefore, the possibility has long been entertained that one might effectively use adoptive immunotherapy as an adjunct to chemotherapy to specifically destroy residual tumor cells remaining after chemotherapy. During the past several years, we and others have shown that some antigenic, syngeneic, advanced tumors can indeed be eradicated by a combination of nonlethal noncurative chemotherapy and adoptive immunotherapy, and that the results can be sufficiently reproducible to enable us to ask some questions about the prerequisites for efficacy. At this point, it must be emphasized that one cannot assume conclusions, e.g., concerning effector cells or mechanisms, drawn

Combination transurethral resection, systemic chemotherapy, and pelvic radiotherapy for invasive (T2–T4) bladder cancer unsuitable for cystectomy: a phase I/II southwestern oncology group study

OBJECTIVES Primarily to evaluate the toxicity and, secondarily, the tumor response and patient survival associated with a three-phase combined modality treatment plan for patients with invasive transitional cell carcinoma (TCC) of the bladder (T2-T4,NX-N2, MO) who are medically unsuitable for or who refuse cystectomy. METHODS Eligible patients initially underwent extensive transurethral resection (TUR) of the primary tumor with the attempt to resect disease totally. Subsequently, they received systemic combination chemotherapy consisting of two cycles of methotrexate, cisplatin, and vinblastine (MCV), followed by cystoscopic re-evaluation of the bladder tumor. Patients then received 6480 cGy radiotherapy to the bladder with concurrent systemic cisplatin. Toxicity, primary tumor response, and overall survival were evaluated. RESULTS Of 34 eligible patients, 27 patients completed the treatment series. Twenty-two received 80% to 100% of the prescribed doses of MCV and only 2 patients experienced grade 4 hematologic toxicities. The most common toxicities were gastrointestinal (23), hematologic (21), and renal (8). The complete response (CR) rate after all treatment phases was 56% (19 of 34), 10 patients achieving a complete tumor resection of visible tumor at the initial TUR of the bladder (TURB); 3, a CR after MCV; and 6, after radiotherapy and concomitant cisplatin. The median overall survival was 21 months with 6 of 34 (18%) alive at 57 months (range, 36 to 75). Complete resection of tumor by TURB was associated with prolonged overall survival. The bladder was the initial site of recurrence in 85% of patients who had achieved a CR status. CONCLUSIONS This older age patient group tolerated this combined modality therapy with acceptable toxicities, but the overall survival rate was not improved compared with those reported with radiotherapy alone.

4,000 RAD preoperative irradiation followed by prompt radical cystectomy for invasive bladder carcinoma: a prospective study of patient tolerance and pathologic downstaging.

The initial National Bladder Cancer Collaborative Group A experience with 4,000 rad adjuvant preoperative radiation therapy followed promptly (within 1 to 28 days) by radical cystectomy and urinary diversion in patients with muscle-invading bladder cancer was monitored prospectively with respect to tolerance of radiation therapy, early postoperative complications and pathologic downstaging. All patients completed the scheduled megavoltage irradiation with, at most, only mild intestinal, urinary or hematologic toxicity. In addition, 86 per cent of the patients completed planned radical cystectomy, with a median interval between radiation therapy and surgery of 13.6 days. No patient died postoperatively. Of the patients 69 per cent recovered with no postoperative complications, while 18 per cent had 1, 9 per cent had 2 and 4 per cent had 3 complications. Pathologic downstaging occurred in 39 per cent of the patients: the disease was downstaged to stage pT0 in 24 per cent and to stage pT1 or pTIS in 15 per cent. Of the patients with an interval of 13 days or less between radiation therapy and surgery the disease was downstaged to stage pT0 in 20 per cent and 63 per cent had no postoperative complications. In patients with an interval of more than 13 days the disease was downstaged in 30 per cent and 76 per cent had no postoperative complications. The results support our rationale for selecting this regimen of adjuvant full dose preoperative radiation therapy, which can shorten the interval between diagnosis and cystectomy, while allowing for the possibility of pathologic downstaging and a radiation dose that is likely to sterilize unresected pelvic micrometastases.

Combined modality therapy for advanced, diffuse lymphocytic and histiocytic lymphomas

Forty‐six previously untreated patients with advanced aggressive non‐Hodgkins (34 poorly differentiated and mixed diffuse, 8 histiocytic and 4 undifferentiated) were treated with a 3 phase combined modality program employing cyclophosphamide (C), hydroxyl‐daunomycin (H), vincristine (O), prednisone (P), procarbazine (P) [CHOP(P)] combination chemotherapy in an initial induction phase, radiotherapy and nonmarrow toxic chemotherapy as a second consolidation phase, followed by a third phase of CHOP(P) chemotherapy for four more cycles. Long‐term maintenance therapy was not given. High dose involved field radiation in phase II was limited to volumes encompasing less than 50% of the marrow bearing skeleton. The large majority of patients (82%) had such widespread involvement that this limitation precluded the use of local radiation and were treated instead with a mean of 132 rad of fractionated total body irradiation (TBI). Thirty‐eight patients (83%) achieved complete remission. Twenty‐nine (66%) of the 44 patients evaluable for follow‐up, and 22 (61%) of the 36 patients receiving TBI, remain alive in complete remission for observation periods of up to 26 months. Cancer 42:1697–1704, 1978.

Autologous Red Blood Cell and Platelet Engulfment in Hairy Cell Leukemia

Seven cases of hairy cell leukemia (leukemic reticulo-endotheliosis) are presented in which peripheral blood or splenic hairy cells or both were identified engulfing autologous red blood cells or platelets. In 3 patients, approximately 5-15% of their peripheral blood hairy cells were engulfing red cells and platelets. In 2 patients, intercellular junctions were present between processes of hairy cells and were similar to processes occasionally seen connecting Langerhans cells to each other. Also, parallel tubular arrays were identified in the cytoplasm of hairy cells from 2 other patients. We conclude that autologous red blood cell and platelet engulfment is a common finding in hairy cell leukemia.

Induction of increased graft-versus-host disease by mouse spleen cells sensitized in vitro to allogeneic tumor.

The aim of our study was to sensitize cells in vitro, follow their proliferative and cytotoxic responses, and determine their ability to cause lethal graft-versus-host disease (GVHD). C57BL/6 (H2b) spleen cells were incubated with irradiated BALB/C (H2d) Moloney lymphoma cells (LSTRA) in mixed leukocyte culture conditions for 2, 4, or 6 days and then tested. The maximal proliferative response occurred after 4 days. In vitro cytotoxic reactivity against 51Cr-labeled LSTRA was generated by 4 days (76.3 \pm 3.1% 51Cr released) and 6 days (133.0 \pm 4.8%) of sensitization but not by 2 days (-0.2 \pm 1.1%). Induction of fatal GVHD was assayed by injecting graded doses of the C57BL/6 spleen cells i.v. into adult BALB/c mice pretreated with cyclophosphamide, 180 mg/kg. Cells sensitized for 2 days were effective but no more so than were (control) cells cultured with irradiated C57BL/6 spleen cells. However, cells sensitized longer were far more active than the control cells. Cells sensitized for 4 days killed 70 of 88 mice (80%), and those sensitized for 6 days killed 37 of 48 mice (77%), whereas control cells killed only 42 of 90 mice (47%) (P < 0.005). Thus, cells sensitized in vitro exhibited an increased ability to induce GVHD in vivo, which was temporally associated with the development of cytotoxicity in vitro.

Reduction of fatal graft-versus-host disease by 3H-thymidine suicide of donor cells cultured with host cells.

The effect of the tritiated thymidine (3H-TdR) suicide technique on the ability of donor cells to induce fatal graft-versus-host disease (GVHD) was studied. C57BL/6 (H-2b) spleen cells were stimulated in vitro with irradiated BALB/c (H-2d) Moloney lymphoma cells in mixed culture and 3H-TdR of high-specific activity added to eliminate proliferating cells. The ability of such cells to induce fatal GVHD was assayed by injecting them i.v. into adult BALB/c mice immunosuppressed with cyclophosphamide (180 mg/kg). These cells induced fatal GVHD in fewer mice (52%) than did C57BL/6 cells cultured with BALB/c lymphoma cells but without 3H-TdR (87%) and C57BL/6 cells cultured with irradiated C57BL/6 cells with (95%) or without 3H-TdR (86%). Thus, the 3H-TdR suicide technique greatly diminished the ability of cells to induce lethal GVHD.