Annals of Surgical Oncology Sign the Guestbook
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsueh, E. C.
Right arrow Articles by Morton, D. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsueh, E. C.
Right arrow Articles by Morton, D. L.
Related Collections
Right arrow Immunology
Annals of Surgical Oncology 9:486-492 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Active Immunotherapy by Reinduction With a Polyvalent Allogeneic Cell Vaccine Correlates With Improved Survival in Recurrent Metastatic Melanoma

Eddy C. Hsueh, MD, Richard Essner, MD, Leland J. Foshag, MD, Wei Ye, MS and Donald L. Morton, MD, FACS

From the Sonya Valley Ghidossi Vaccine Laboratory of the Roy E. Coats Research Laboratories of the John Wayne Cancer Institute, St. John’s Health Center, Santa Monica, California.

Correspondence: Address correspondence and reprint requests to: Eddy C. Hsueh, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404; Fax: 310-449-5261; E-mail: hsuehe{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: We have observed prolonged survival in patients undergoing vaccine reinduction after resection of recurrent metastatic melanoma and adjuvant polyvalent allogenic cell vaccine (PACV) immunotherapy. We hypothesized that reinduction with a more intensive vaccine regimen would re-stimulate specific immune responses that were correlated with survival after recurrence.

Methods: From 1996 to 1998, 194 patients developed recurrence during adjuvant PACV (CancerVax vaccine) treatment after resection of metastatic melanoma. Recurrent disease was treated with or without vaccine reinduction. Reinduction regimen entailed an increased vaccine frequency and coadministration of two doses of bacille Calmette-Guérin (BCG). PACV Delayed-type hypersensitivity (DTH) responses were prospectively recorded. Survival was defined as the interval from recurrence to death.

Results: Ninety-four patients underwent reinduction immunotherapy. DTH responses to PACV before recurrence increased significantly after reinduction therapy (P = .0001). The median survival time was 37 months for reinduced patients and 17 months for other patients. On multivariate analysis, reinduction status remained a significant prognostic variable (P = .0277). In the reinduction group, there was a significant correlation between PACV DTH responses and survival (P = .0178).

Conclusions: Reinduction vaccine regimen can enhance immune responses in previously immunized patients and is associated with prolonged survival after recurrence in patients receiving the same active specific immunotherapy.

Key Words: Melanoma • Immunotherapy • Reinduction • Tolerance


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Melanoma cells are immunogenic. The presence of melanoma tumors in patients can induce endogenous immune responses against antigens present on the melanoma cells.1–4 In rare cases, the immune responses of the tumor-bearing host have been implicated in the spontaneous regression of melanoma metastases.5 Because of these unique properties associated with melanoma, multiple investigators have evaluated immunomodulatory regimens as postsurgical adjuvant therapy or primary therapy for patients with metastatic melanoma.6–9 The goal of these approaches is to induce cytotoxic antibody, cellular immune responses, or both against the tumor antigens present on the patient’s melanoma cells.

In 1985 our group began a series of phase I/II studies examining the clinical safety and efficacy of a polyvalent allogeneic irradiated whole-cell vaccine (PACV) in patients with high-risk melanoma.10–12 The current formulation of our PACV (CancerVax vaccine; CancerVax Corp., Carlsbad, CA) is undergoing phase III clinical trial evaluation as an adjuvant therapy after resection of regional nodal and limited distant metastatic melanoma. This PACV can induce antibody as well as cellular immune responses against multiple tumor antigens present on melanoma cells.13–16 We have reported a significant correlation between the magnitude of antibody and cellular immune responses to the vaccine and the overall survival (OS) of patients receiving adjuvant therapy with PACV after surgical resection of American Joint Committee on Cancer (AJCC) stage III and IV melanoma.13,14,17

We have also noted recurrence in certain patients receiving this vaccine as adjuvant therapy. These patients are fully evaluated radiographically and are considered for intensified vaccine administration (reinduction) to re-stimulate specific antimelanoma immune responses. Because these patients have been exposed to the same antigen mixture before development of their recurrence, they may become tolerant to the tumor antigens present in the vaccine. If this occurs, then reinduction therapy should not induce specific antimelanoma immune responses nor confer survival benefit. However, we have previously reported our experience with a cohort of AJCC stage IV melanoma patients undergoing re-resection of recurrent distant metastases. Patients who received adjuvant therapy with PACV before recurrence and then received reinduction PACV therapy after re-resection had prolonged survival compared with patients who never received the vaccine.18 We therefore hypothesized that PACV reinduction therapy after recurrence might re-stimulate specific antibody or cellular immune responses, or both, that are correlated with survival after recurrence. The results of this study confirm this hypothesis, although the specific immune response to the vaccine was less rigorous at reinduction than initiation.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
From January 1, 1996, to December 31, 1998, 194 patients with AJCC stage III and IV melanoma were enrolled onto adjuvant PACV protocols after complete resection of their melanoma at the John Wayne Cancer Institute. These patients had no clinical or radiographic evidence of disease before vaccine initiation. Excluded were patients receiving chemotherapy, radiotherapy, biologic therapy, or immunological therapy within 30 days of vaccine initiation and those undergoing incomplete resection of their disease. Also excluded were patients who received the vaccine before development or complete resection of regional or distant metastases.

Demographic data were similar between the 94 reinduction patients and the 100 no-reinduction patients (Table 1). Both groups had a preponderance of male patients. However, there was a higher proportion of patients with only one tumor-involved anatomical site in the reinduction group (78%) than in the no-reinduction group (63%). There was also a higher proportion of patients with distant soft tissue, skin, or lymph node involvement (M1a) in the reinduction group (60%) than the no-reinduction group (32%). Surgery was the first-line treatment of recurrence in 53 patients (56%) in the reinduction group and in 26 patients (26%) in the no-reinduction group.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Patient demographics
 
Vaccine Preparation
Our PACV (CancerVax vaccine) is an allogeneic whole-cell vaccine composed of cells from 3 melanoma cell lines expressing at least 20 immunogenic tumor antigens.19 Its preparation is described elsewhere.12 Briefly, cells from M10-V, M24-V, and M101-V lines are grown in tissue culture medium, harvested, washed, and pooled (8 x 106 cells per line; 24 x 106 total cells) under sterile conditions. The cells are then irradiated with 150 Gy and cryopreserved in liquid nitrogen. Before April 30, 1996, 10% dimethyl sulfoxide, used in cryopreservation, was washed out of all three lines after thawing, and the cells were reconstituted in RPMI 1640 before injection; each line was kept in a separate vial. Since April 30, 1996, a new preparation has been used in which cells from the three lines are cryopreserved together in a smaller volume (.5 mL) and reconstituted with the addition of .5 mL of saline. Five percent dimethyl sulfoxide is present in this PACV. The vaccine is administered immediately after thawing.

Protocol
The patients reported here were on a series of protocols that differed only in the use of different immunoadjuvant doses of bacille Calmette-Guérin (BCG). Before treatment, all patients underwent skin testing with purified protein derivative (PPD). The standard therapy consisted of intradermal injections of 1.0 mL of reconstituted PACV in two sites in each of following four areas: left or right hypogastrium and left or right upper lateral truncal regions. The vaccine was given every 2 weeks x 5 and then monthly x 10 for the first year of treatment. After 1 year, the vaccination interval was every 3 months x 4 and then every 6 months x 6 for 5 years. For the first two treatments, the vaccine was mixed with the Tice strain BCG. The dose of BCG in the first injection was 2.7 to 10.8 x 106 colony-forming units (cfu) for PPD-negative patients and half that much for PPD-positive patients. The dose of BCG in the second injection was half the initial BCG dose. Follow-up clinical and laboratory evaluations were repeated monthly, with chest x-rays at least every 3 months for the first 2 years. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 before enrollment. After appropriate discussion and before enrollment, informed consent was obtained.

At the time of recurrence, patients underwent full metastatic work-up with magnetic resonance imaging of the brain and computed tomography of the chest, abdomen, and pelvis. Reinduction therapy with PACV was undertaken in patients who consented to further vaccine treatment. The reinduction regimen consisted of two biweekly vaccine injections. The first dose was administered with 20,000 to 50,000 cfu of BCG, and the second dose was administered with 10,000 to 25,000 cfu of BCG. Patients subsequently received monthly injections of the vaccine for up to 1 year and then received the vaccine in the second- to fifth-year injection schedule described previously. The joint investigational review board of John Wayne Cancer Institute and Saint John’s Health Center approved all of the above-mentioned protocols.

Assessment of Immunological Response
Before vaccine therapy and at each vaccine administration, a dose of 2.4 x 106 vaccine cells (one tenth of the vaccination dose) was given at a separate intradermal site for assessing delayed-type hypersensitivity (DTH) response. DTH response to the vaccine was determined 48 hours later. The control DTH response to nonmelanoma-associated antigens was monitored by administering a PPD skin test to PPD-negative patients at monthly intervals until the patient became PPD positive. The DTH responses were prospectively collected and entered into our melanoma vaccine database.

Statistical Analysis
Survival curves were estimated with the Kaplan-Meier method. The log-rank test was used for univariate analysis of categorical variables to determine differences between curves. Univariate analysis of continuous variables was performed by using the Cox proportional hazard regression method. OS was defined as the period between recurrence and death. Multivariate analysis was performed by Cox proportional hazard regression. When applicable, the signed rank sum test was used to test the relationship between subgroups. A P value of <.05 was considered significant. All statistical analyses were two tailed and were performed with SAS software (SAS Institute, Inc., Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Immunological Responses After Reinduction With PACV
Of the 194 study patients, 94 underwent reinduction, and 100 did not. Before the development of recurrence, the DTH responses to PACV were comparable in both groups. The baseline DTH response to PACV before vaccine therapy and the maximum DTH response to PACV within the first 16 weeks of immunization were 4.7 ± 5.4 mm (mean ± SD) and 17.3 ± 10.3 mm, respectively, in the reinduction group (P = .0001) and 5.3 ± 5.9 mm and 15 ± 10.1 mm, respectively, in the no-reinduction group (P = .0001).

In the reinduction group, the mean DTH response to PACV of 9.7 ± 6.6 mm before recurrence increased to a maximum of 14.1 ± 9.7 mm after the start of reinduction therapy (P = .0001; Fig. 1). However, this increase was significantly less than the original increase during the first 16 weeks of vaccine therapy (17.3 ± 10.3 mm; P = .0001).



View larger version (41K):
[in this window]
[in a new window]
  		FIG. 1. Temporal delayed-type hypersensitivity (DTH) responses to polyvalent allogeneic cell vaccine (PACV) in patients undergoing reinduction.

 
Of the 94 reinduction patients, 53 underwent reinduction after complete surgical resection of recurrent disease, and 41 underwent reinduction in conjunction with other nonsurgical treatment. There was no significant difference in the maximum DTH response to vaccine reinduction between the surgical group (13.6 ± 9.5 mm) and the nonsurgical group (14.7 ± 10 mm; P = .6373; Fig. 2). This suggests that tumor burden, which was lower in the surgical group than the nonsurgical group, did not have a significant effect on the response to reinduction immunotherapy.



View larger version (42K):
[in this window]
[in a new window]
  		FIG. 2. Delayed-type hypersensitivity (DTH) responses to polyvalent allogeneic cell vaccine reinduction in patients who received surgical versus nonsurgical treatment for recurrence. AWD, alive with disease; NED, no evidence of disease.

 
OS Analysis
The median follow-up time was 20 months (range, 30 to 68 months for survivors). Univariate analysis showed a significant difference in OS for patients with one versus more than one site of recurrence (P = .0037) and for patients with visceral (M1b) versus distant skin, soft tissue, or nodal (M1a) recurrence (P = .0144; Table 2).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Correlation of clinical variables with overall survival
 
The median OS and 3-year OS rate from the time of recurrence for the reinduction group were 37 months and 52%, respectively, in contrast to 17 months and 30%, respectively, for the no-reinduction group (P = .0002; Fig. 3). Because patients in the reinduction group were more likely to have undergone complete surgical resection and have only one site of recurrence, the OS of surgical patients in the no-reinduction group (group 1) was compared with the OS of surgical patients in the reinduction group (group 2). Univariate analysis showed no significant difference in OS between group 1 (n = 26) and group 2 (n = 53; P = .6199; Fig. 4). A similar analysis was used to compare the OS for nonsurgical patients in the no-reinduction and reinduction groups (group 3 and group 4, respectively). There was a significant difference between group 3 (n = 74) and group 4 (n = 41; P = .0046); the median OS was 7 months in group 3 versus 21 months in group 4 (Fig. 5).



View larger version (30K):
[in this window]
[in a new window]
  		FIG. 3. Correlation of overall survival with polyvalent allogeneic cell vaccine reinduction status. Survival curves were estimated by the Kaplan-Meier method. The black line represents reinduction patients (n = 94), and the gray line represents no-reinduction patients (n = 100; P = .0002).

 


View larger version (22K):
[in this window]
[in a new window]
  		FIG. 4. Correlation of overall survival with polyvalent allogeneic cell vaccine reinduction status in patients undergoing surgical treatment for their recurrence. Survival curves were estimated by the Kaplan-Meier method. The black line represents reinduction patients (n = 53), and the gray line represents no-reinduction patients (n = 26; P = .6199). Median survival was not reached for either group. The 1-year overall survival rate was 87% for reinduction patients and 72% for no-reinduction patients.

 


View larger version (26K):
[in this window]
[in a new window]
  		FIG. 5. Correlation of overall survival with polyvalent allogeneic cell vaccine reinduction status in patients undergoing nonsurgical treatment for their recurrence. Survival curves were estimated by the Kaplan-Meier method. The black line represents reinduction patients (n = 41), and the gray line represents no-reinduction patients (n = 74; P = .0046). The median survival times were 20 months for reinduction patients and 7 months for no-reinduction patients.

 
Multivariate analysis considering age, sex, site of metastases (M1a, M1b, and M1a and b), number of involved organ sites, surgical resection of recurrence, and reinduction status confirmed reinduction status as an important independent prognostic variable (P = .0277; Table 2). Stronger reinduction DTH responses to PACV (on the basis of a previously determined cutoff of 10 mm17) were correlated with OS (P = .0178; Fig. 6).



View larger version (28K):
[in this window]
[in a new window]
  		FIG. 6. Correlation of overall survival with delayed-type hypersensitivity (DTH) responses to polyvalent allogeneic cell vaccine after reinduction. Survival curves were estimated by the Kaplan-Meier method. The black line represents patients with a DTH of >=10 mm (n = 56), and the gray line represents patients with a DTH of <10 mm (n = 38; P = .0178).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In this study, patients who developed recurrent melanoma while undergoing PACV immunotherapy were treated with a more intensive vaccine regimen that re-stimulated specific immune responses to the vaccine. These responses were correlated with OS, a finding in agreement with our previously reported study of immune responses in patients with no prior exposure to our PACV.13–15,17 However, DTH responses after reinduction were lower than the DTH responses that had previously been achieved during the initial 16 weeks of PACV therapy.

Recurrence during a specific therapy usually indicates tumor resistance and suggests that further treatment with the same therapy will not improve clinical outcome. However, the results of this study indicate that this may not be true for specific immunotherapy. Although the specific immune response (DTH response to PACV) was lower after reinduction than initiation, the significantly longer OS in the reinduction group strongly suggests that reinduction should be considered in the management of recurrence. The reason for the prolonged survival associated with reinduction is not clear but may reflect the polyvalent nature of our vaccine; multiple tumor antigens on PACV cells should minimize the likelihood of a recurrent tumor that does not express any of the antigens expressed by the vaccine. We speculate that the development of recurrence in patients receiving PACV immunotherapy is probably due to lower levels of circulating cytotoxic lymphocytes or antibodies at the time of immunization. If this is so, then re-stimulation of the patient’s cytotoxic lymphocytes or antibodies with a more intensive immunization regimen (reinduction) might result in prolonged survival.

Most of the current immunotherapeutic approaches to melanoma target tumor antigens that can also be found in normal tissue (self-antigens).16,20,21 Preexisting tolerance to these antigens is necessary to prevent autoimmunity and destruction of normal tissue. Various immunomodulatory manipulations can overcome this tolerance and induce immune responses to these self-antigens. Although there is no randomized phase III trial validating the clinical efficacy of these immunotherapeutic approaches in melanoma, results of our phase I and II studies strongly suggest a survival benefit associated with administration of our irradiated PACV.11,12,22 Specific immune responses to this vaccine are correlated with OS after the initiation of vaccine therapy.13,14,17 The immune responses presumably target tumor antigens that are also found in normal tissue, i.e., self-antigens.

The fact that all patients have some level of tolerance to the vaccine (or to any immunotherapy based on antigens shared by normal and malignant tissue) suggests that the response to PACV therapy is a direct function of the patient’s level of immune surveillance. Decreased immune surveillance, i.e., increased tolerance, may decrease the specific immune response to the vaccine and thereby allow tumor cell growth and clinical recurrence. In this study, a significant increase in the DTH response to PACV after reinduction suggests that the tolerance to this antigenic challenge can be overcome in part by simply intensifying the immunotherapeutic regimen. However, the maximum response seems to be somewhat reduced (17 vs. 14 mm). Thus, the level of DTH response to the vaccine after reinduction was slightly less than that observed in patients previously unexposed to this vaccine. This is in marked contrast to reimmunization against infectious disease, which induces responses that are stronger than the initial responses.23 It is possible that adding other immunomodulatory agents to the PACV reinduction regimen might produce a more dramatic and sustained elimination of tolerance to antigens in the vaccine.

The OS after recurrence was associated with the number of tumor-involved organ sites and the site of metastases, consistent with data previously reported by our group and other investigators.24–29 Consideration of the significant difference in OS between the reinduction and no-reinduction groups must take into account the higher proportion of reinduction patients who had only one site of disease, who had M1a involvement, or who underwent complete resection of recurrence. The prognostic significance of reinduction was confirmed on multivariate analysis considering these other important clinical variables, such as organ site of involvement, number of sites involved, and surgical resection of recurrence. Although there was no significant difference in OS for no-reinduction versus reinduction among the surgical patients, this may be due to the small sample size. In contrast, when only the nonsurgical patients were considered, reinduction still conferred a significant survival advantage.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
In conclusion, reinduction with PACV active specific immunotherapy after recurrence can re-stimulate specific immune responses to the vaccine. The significant correlation between postrecurrence survival and reinduction therapy suggests the potential efficacy of this approach for treatment of recurrent metastatic melanoma.


   Acknowledgments
 
Supported by grants CA87071 and CA12582 from the National Cancer Institute and by funding from the Wayne and Gladys Valley Foundation (Oakland, CA).


   Footnotes
 
Presented at the Society of Surgical Oncology annual meeting, Washington, DC, March 15–18, 2001.

Received for publication April 17, 2001. Accepted for publication November 7, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Morton DL, Malmgren RA, Holmes EC, Ketcham AS. Demonstration of antibodies against human malignant melanoma by immunofluorescence. Surgery 1968; 64: 233–40.[Medline]
  2. Lewis MG, Ikonopisov RL, Nairn RC, et al. Tumour-specific antibodies in human malignant melanoma and their relationship to the extent of the disease. BMJ 1969; 3: 547–52.
  3. Bodurtha AJ, Chee DO, Laucius JF, et al. Clinical and immunological significance of human melanoma cytotoxic antibody. Cancer Res 1975; 35: 189–93.[Abstract/Free Full Text]
  4. Hsueh EC, Gupta RK, Yee R, et al. Does endogenous immune response determine the outcome of surgical therapy for metastatic melanoma? Ann Surg Oncol 2000; 7: 232–8.[Abstract]
  5. Everson TC. Spontaneous regression of cancer. Ann N Y Acad Sci 1964; 114: 721–35.[Medline]
  6. Berd D. Autologous, hapten-modified vaccine as a treatment for human cancers. Vaccine 2001; 19: 2565–70.[CrossRef][Medline]
  7. Bystryn JC. Vaccines for melanoma. Design strategies and clinical results. Dermatol Clin 1998; 16: 269–75.[CrossRef][Medline]
  8. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4: 321–7.[CrossRef][Medline]
  9. Wallack MK, Sivanandham M, Balch CM, et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. J Am Coll Surg 1998; 187: 69–77.[CrossRef][Medline]
  10. Morton DL, Barth A. Vaccine therapy for malignant melanoma. CA Cancer J Clin 1996; 46: 225–44.[Medline]
  11. Morton DL, Foshag LJ, Hoon DSB, et al. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann Surg 1992; 216: 463–82.[Medline]
  12. Hsueh EC, Nathanson L, Foshag LJ, et al. Active specific immunotherapy with polyvalent melanoma cell vaccine in patients with in-transit melanoma metastases. Cancer 1999; 85: 2160–69.[CrossRef][Medline]
  13. Hsueh EC, Gupta RK, Qi K, et al. Correlation of specific immune responses with survival in patients receiving melanoma cell vaccine. J Clin Oncol 1998; 16: 2913–20.[Abstract/Free Full Text]
  14. Hsueh EC, Famatiga E, Gupta RK, et al. Enhancement of complement-dependent cytotoxicity by melanoma cell vaccine: correlation with disease-free survival. Ann Surg Oncol 1998; 5: 595–602.[Abstract]
  15. Takahashi T, Johnson TD, Nishinaka Y, et al. IgM anti-ganglioside antibodies induced by melanoma cell vaccine correlate with survival of melanoma patients. J Invest Dermatol 1999; 112: 205–9.[CrossRef][Medline]
  16. Okamoto T, Irie RF, Fujii S, et al. Anti-tyrosinase-related protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy. J Invest Dermatol 1998; 111: 1034–9.[CrossRef][Medline]
  17. Jones RC, Kelley M, Gupta RK, et al. Immune response to polyvalent melanoma cell vaccine in AJCC stage III melanoma: an immunologic survival model. Ann Surg Oncol 1996; 3: 437–45.[Abstract]
  18. Ollila DW, Hsueh EC, Stern SL, Morton DL. Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 1999; 71: 209–13.[CrossRef][Medline]
  19. Chan AD, Morton DL. Active immunotherapy with allogeneic tumor cell vaccines: present status. Semin Oncol 1998; 25: 611–22.[Medline]
  20. Kawakami Y, Suzuki Y, Shofuda T, et al. T cell immune responses against melanoma and melanocytes in cancer and autoimmunity. Pigment Cell Res 2000; 13 (Suppl 8): 163–9.
  21. Yee C, Thompson JA, Roche P, et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo. J Exp Med 2000; 192: 1637–44.[Abstract/Free Full Text]
  22. Morton DL, Ollila DW, Hsueh EC, et al. Cytoreductive surgery and adjuvant immunotherapy: a new management paradigm for metastatic melanoma. CA Cancer J Clin 1999; 49: 101–16.[Abstract]
  23. Roitt I, Brostoff J, Male D. Immunology. 5th ed. Edinburgh: Mosby, 1998.
  24. Feun LG, Gutterman J, Burgess MA, et al. The natural history of resectable metastatic melanoma (stage IVA melanoma). Cancer 1982; 50: 1656–63.[CrossRef][Medline]
  25. Overett TK, Shiu MH. Surgical treatment of distant metastatic melanoma: indications and results. Cancer 1985; 56: 1222–30.[CrossRef][Medline]
  26. Karp NS, Boyd A, DePan HJ, et al. Thoracotomy for metastatic malignant melanoma of the lung. Surgery 1990; 107: 256–61.[Medline]
  27. Branum GD, Seigler HF. Role of surgical intervention in the management of intestinal metastases from malignant melanoma. Am J Surg 1991; 162: 428–31.[CrossRef][Medline]
  28. Karakousis CP, Velez A, Driscoll BA. Metastasectomy in malignant melanoma. Surgery 1994; 115: 295–302.[Medline]
  29. Fletcher WS, Pommier RF, Lum S, et al. Surgical treatment of metastatic melanoma. Am J Surg 1998; 175: 413–7.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 JCOHome page
E. C. Hsueh, R. Essner, L. J. Foshag, D. W. Ollila, G. Gammon, S. J. O'Day, P. D. Boasberg, S. L. Stern, X. Ye, and D. L. Morton
Prolonged Survival After Complete Resection of Disseminated Melanoma and Active Immunotherapy With a Therapeutic Cancer Vaccine
J. Clin. Oncol., December 1, 2002; 20(23): 4549 - 4554.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsueh, E. C.
Right arrow Articles by Morton, D. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsueh, E. C.
Right arrow Articles by Morton, D. L.
Related Collections
Right arrow Immunology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS