Amphetamines are useful for supporting cancer patients with fatigue.

Amphatamines are occasionally used by oncologists to manage opioid side effects or to treat cancer fatigue. Methylphenidate (Ritalin®; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is a central nervous system (CNS) stimulant that is structurally related to amphetamines. A recent publication found seven clinical trials (22%) of methylphenidate for the treatment of Cancer Related Fatigue. Although methylphenidate was shown to improve fatigue in these open-label studies in patients with cancer, its effect was not significantly different from that of placebo in a double-blind study. However, a recent randomized placebo-controlled trial in nonanemic patients with cancer who had completed chemotherapy showed that dexmethylphenidate (Focalin®; Novartis, an almost identical drug,) was associated with significantly greater improvements in fatigue than placebo. Given that relatively few randomized, placebo-controlled clinical trials have been conducted specifically to evaluate the use of psychostimulants in patients with Cancer Related Fatigue, adverse effects of psychostimulants, such as irritability, anorexia, insomnia, labile mood, nausea, and tachycardia, should be considered when making treatment decisions. On the basis of Phase II and randomized studies supporting Ritalin, I consider it medically necessary.

Trescot AM, Boswell MV, Atluri SL, Hansen NC, Deer TR, Abdi S, Jasper JF, Singh V, Jordan AE, Johnson BW, Cicala RS, Dunbar EE, Helm S II, Varley KG, Suchdev PK, Swicegood JR, Calodney AK, Ogoke BA, Minore WS, Manchikanti L. Opioid guidelines in the management of chronic non-cancer pain. Pain Phys 2006;9(1):1-39. [350 references]

Jennifer K. Carroll et al, Pharmacologic Treatment of Cancer-Related Fatigue, The Oncologist, Vol. 12, No. suppl_1, 43-51, May 2007;

Mark Rozans, Albert Dreisbach, Juan J.L. Lertora, Marc J. KahnPalliative Uses of Methylphenidate in Patients With Cancer: A Review Journal of Clinical Oncology, Vol 20, Issue 1 (January), 2002: 335-339

nccn, supportive care, cacner fatigue, 2012

Susan E. Hardy, Methylphenidate for Treatment of Depressive Symptoms, Apathy, and Fatigue in Medically Ill Older Adults and Terminally Ill Adults Am J Geriatr Pharmacother. 2009 February; 7(1): 34–59.

Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA.
Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s Macroglobulinemia.Semin Oncol. 2003 Apr;30(2):110-5.

Dimopoulos MA, Panayiotidis P, Moulopoulos LA, et al: Waldenstrom’s macroglobulinemia: clinical features, complications, and management. J Clin Oncol 2000 Jan; 18(1): 214-26

Dimopoulos MA, Galani E, Matsouka C: Waldenstrom’s macroglobulinemia. Hematol Oncol Clin North Am 1999 Dec; 13(6): 1351-66

The technology has been validated in the sense that the CellSearch system enables the reliable detection of CTCs in blood and is suitable for the routine assessment of metastatic breast cancer patients in the clinical laboratory. Several studies show that serial estimation of CTC level up to 20 weeks correlates with progression-free and overall survival. This suggests that elevated CTC level at any time during therapy can reflect disease progression and mortality risk for MBC patients. Another subset analysis was done on 83 (of the 177) patients who were receiving first-line treatment for metastatic disease. CTC level was assessed in these patients at baseline and monthly thereafter for up to 6 months, for a median follow-up of 12.2 months. CTC levels before and after starting therapy were strong, independent prognostic factors for both progression-free and overall survival. It has not been proven, however, that it is a tool that improves clinical care.

Allard WJ, Matera J, Miller MC, et al: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897-6904, 2004.

Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.

Hayes DF, Cristofanilli M, Budd GT, et al: Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12:4218-4224, 2006.

Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: A novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23:1420-1430, 2005.

Riethdorf, Sabine, Fritsche, Herbert, Muller, Volkmar, Rau, Thomas, Schindlbeck, Christian, Rack, Brigitte, Janni, Wolfgang, Coith, Cornelia, Beck, Katrin, Janicke, Fritz, Jackson, Summer, Gornet, Terrie, Cristofanilli, Massimo, Pantel, Klaus
Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System
Clin Cancer Res 2007 13: 920-928

On the other hand, the pathologic features of infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapy argue that it is neoplastic process. In addition, X chromosome–linked DNA probes appear to demonstrate a degree of monoclonality. Monoclonality is an important attribute of cancer but it does not prove that a proliferative process is neoplastic. Specific and unique cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.

Activating mutation of a protooncogen in the Raf family, the BRAF gene, was recently detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%) and two other studies showed a similar result. Presence of this activating mutation could support the notion that LCH s a precancerous condition or a myelodysplastic disorder.

Allen CE, Flores R, Rauch R, et al.: Neurodegenerative central nervous system Langerhans cell histiocytosis and coincident hydrocephalus treated with vincristine/cytosine arabinoside. Pediatr Blood Cancer 54 (3): 416-23, 2010. [PUBMED Abstract]

Minkov M, Grois N, Broadbent V, et al.: Cyclosporine A therapy for multisystem langerhans cell histiocytosis. Med Pediatr Oncol 33 (5): 482-5, 1999. [PUBMED Abstract]

Willman CL, Busque L, Griffith BB, et al. Langerhans’-cell histiocytosis (histiocytosis X)–a clonal proliferative disease. N Engl J Med 1994;331:154-60

Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010.

Michael Girschikofsky, Maurizio Arico, Diego Castillo, Anthony Chu, Claus Doberauer, Joachim Fichter, Julien Haroche, Gregory A Kaltsas, Polyzois Makras, Angelo V Marzano, Mathilde de Menthon, Oliver Micke, Emanuela Passoni, Heinrich M Seegenschmiedt, Abdellatif Tazi & Kenneth L McClain Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net Orphanet Journal of Rare Diseases volume 8, Article number: 72 (2013

Tazi A, Marc K, Dominique S, de Bazelaire C, Crestani B, Chinet T, Israel-Biet D, Cadranel J, Frija J, Lorillon G, Valeyre D, Chevret S:Serial CT and lung function testing in pulmonary Langerhans cell histiocytosis. Eur Respir J. 2012, 40 (4): 905-912.

Read the Layperson version here.

There is evidence to recommend platinum-based chemotherapy regimens as post-operative adjuvant therapy in the management of patients with completely resected stage II and IIIA NSCLC. Cisplatin-based treatment is preferred, although a carboplatin-based regimen can be used as an alternative if there is a contraindication to cisplatin. There is uncertainty about a benefit to patients with resected stage IB NSCLC, although adjuvant chemotherapy may still be considered in selected individuals.

A meta-analysis published in 1995 indicated that post-operative chemotherapy did not significantly reduce the risk of death in surgically resected, pathologic stage IB, II and IIIA NSCLC, although there was a trend in favour of adjuvant chemotherapy regimens that included the agent cisplatin.

Only chemotherapy regimens used in the most recent trials are evidence-based. These include the combination of cisplatin and vinorelbine as standard, as these two agents were employed in IALT, NCIC CTG BR.10 and ANITA. Cisplatin-based treatment is preferred, but in individuals with a contraindication to cisplatin, the combination of carboplatin and paclitaxel is an acceptable alternative.

References:

1. Douillard J, Rosell R, Delena M, Legroumellec A, Torres A, Carpagnano F. ANITA: phase III adjuvant vinorelbine and cisplatin versus observation in completely resected (stage I-III) non-small cell lung cancer patients: final results after 70-month median follow-up. J Clin Oncol 2005; 23 Suppl 16S: 624s.
2. Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH, for the Eastern Cooperative Oncology Group. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. N Engl J Med 2000; 343: 1217-1222.
3. Logan DM, Lochrin CA, Darling G, Eady A, Newman TE, Evans WK and the Lung Cancer Disease Site Group. Adjuvant radiotherapy and chemotherapy in stage II or IIIA non-small cell lung cancer after complete resection. Cancer Prevent Control 1997; 1: 366-378.
4. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995; 311: 899-909.
5. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Le Chevalier T. Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients. Proc Am Soc Clin Oncol 2006 Part I: abstr 7008.
6. Scagliotti GV, Fossati R, Torri V, Crino L, Giaccone G, Silvano G, Martelli M, Clerici M, Cognetti F, Tonato M. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer. J Natl Cancer Inst 2003; 95: 1453-1461.
7. Strauss GM, Herndon J, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RL, Green MR. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. Proc Am Soc Clin Oncol 2004; abstr 7019.
8. Strauss GM, Herndon JE, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RA, Vokes EE, Green MR. Adjuvant chemotherapy in stage IB non-small cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. Proc Am Soc Clin Oncol 2006 Part I: abstr 7007.
9. The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med 2004; 350: 351-360.
10. Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao M, Gandara D, Kesler K, Demmy T, Shepherd F. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589-2597.

Doxorubicin is the most active anticancer agent employed, with useful but temporary responses obtained in as many as 33% of patients with metastatic disease. Paclitaxel also has significant activity.

The combination of doxorubicin plus cisplatin (AP) has produced RRs of 40% to 46%, with reported median progression-free survival (PFS) ranging from 5.2 to 7.2 months in the three most recent Gynecologic Oncology Group (GOG) randomized trials. Most recently, the GOG compared AP with doxorubicin plus paclitaxel 150 mg/m2 as a 24-hour continuous infusion with filgrastim support, and there was no statistically significant improvement in objective RR, PFS, or overall survival (OS) between the regimens. The most recent randomized study found that TAP significantly improves RR, PFS, and OS compared with AP. What this suggested is that riplet therapy is superior to doublets. I elaborate. In 2001, the GOG published the results of a dose-finding trial that combined cisplatin, doxorubicin, and a 3-hour infusion of paclitaxel (TAP) in chemotherapy-naïve patients with advanced endometrial carcinoma and other gynecologic malignancies. In that trial, doxorubicin and cisplatin were administered on day 1, and paclitaxel, on day 2 because of previous reports suggesting that the cardiotoxicity associated with the paclitaxel + doxorubicin combination was decreased when these agents were administered 16 to 24 hours apart.12 Even when low doses of the combination of TAP were used, filgrastim was required for hematopoietic support, and neurotoxicity became the dose-limiting toxicity. The recommended phase II doses were doxorubicin 45 mg/m2, cisplatin 60 mg/m2, and paclitaxel 160 mg/m2 intravenously over 3 hours, with filgrastim 5 µg/kg given on days 3 to 12. Of 20 patients treated at this dose level, two (10%) developed grade 3 peripheral neuropathy Next GOG did a phase III trial compared cisplatin plus doxorubicin to doxorubicin, cisplatin, and paclitaxel with granulocyte colony-stimulating factor (G-CSF) support. The three-drug arm produced more objective responses than the two-drug arm (57% vs 34%, P < .01). Progression-free survival was extended to 8.3 months compared with 5.3 months in the control arm (P < .01); and overall survival reached a median of 15.3 months compared with 12.3 months (P < .037). Patients who received doxorubicin plus cisplatin on this trial were not likely to receive paclitaxel as first salvage therapy, which might account for the survival advantage for the three-drug combination. As seen in previous trials, increasing efficacy with more chemotherapy also led to increasing toxicity; patients receiving the three-drug combination were more likely to suffer thrombocytopenia and grade 3 and 4 neurotoxicity. The current GOG phase III trial compares the three-drug regimen of cisplatin, doxorubicin, and paclitaxel with G-CSF support to carboplatin combined with paclitaxel. Phase II trials testing the combination of carboplatin and paclitaxel in advanced, recurrent, or metastatic endometrial cancer have shown response rates of 46% to 78%. A Cochrane review recently attempted to address the issue of whether more chemotherapy is better in the case of treating advanced, recurrent, or metastatic endometrial cancer. Eleven randomized clinical trials were identified that included a total of 2,288 patients. A meta-analysis of six trials showed improved progression-free survival with more intensive chemotherapy compared with less intense chemotherapy (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.71–0.90; P = .004) but a comparable overall survival (HR = 0.90, 95% CI = 0.80–1.03; P = .12). Grade 3 and 4 toxicity, particularly in the form of myelosuppression and gastrointestinal toxicity, was higher in patients receiving more intense chemotherapy regimens. The NCCN lists carboplatin, cisplatin and palcitaxel as options for metastatic or advanced endometrial carcinoma, as single agents or combined. For clinical use, carboplatin is interchangeable with cisplatin by general consensus because of their similarity and trial evidence in a a number of cancer sites (although not in all and not in endometrial cancer). NCCN cites a variety of regimens, including ifosfamide/paclitaxel, doxorubicin/cisplatin/paclitaxel, cisplatin/dosorubicin and the single agents: cisplatin, doxorubicin, paclitaxel and ifosfamide. Cisplatin, etoposide, adriamycin is an older regimen that was found in 1995 to be superior to a melphalan based regimen. It is not currently in any trial for endometrial cancer as per clinicaltrials.gov.

NCCN, Endometrial ENDO-B, 2019

Samarnthai N, Hall K, Yeh IT. Molecular profiling of endometrial malignancies. Obstet Gynecol Int. 2010;2010:162363.

Urick, M.E., Bell, D.W. Clinical actionability of molecular targets in endometrial cancer. Nat Rev Cancer 19, 510–521 (2019)

Sarah M. Temkin, MD, Gini Fleming, MD Current Treatment of Metastatic Endometrial Cancer
Cancer Control. 2009;16(1):38-45.

Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22(11):2159-2166.

Humber CE, Tierney JF, Symonds RP, et al. Chemotherapy for advanced, recurrent or metastatic endometrial cancer: a systematic review of Cochrane collaboration. Ann Oncol. 2007;18(3):409-420.

Wolf K, Slomovitz BM. Novel biologic therapies for the treatment of endometrial cancer. Int J Gynecol Cancer. 2005;15(2):411.

J. T. Thigpen, M. F. Brady, H. D. Homesley, J. Malfetano, B. DuBeshter, R. A. Burger, and S. Liao Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study J. Clin. Oncol., October 1, 2004; 22(19): 3902 – 3908.

G. F. Fleming, V. L. Filiaci, R. C. Bentley, T. Herzog, J. Sorosky, L. Vaccarello, and H. Gallion Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study Ann. Onc., August 1, 2004; 15(8): 1173 – 1178

Cornelison TL, Baker TR, Piver MS, Driscoll DL..Cisplatin, adriamycin, etoposide, megestrol acetate versus melphalan, 5-fluorouracil, medroxyprogesterone acetate in the treatment of endometrial carcinoma.: Gynecol Oncol. 1995 Nov;59(2):243-8

Two randomized clinical trials have been reported that addressed the issue of second-line treatment in patients with advanced NSCLC that progresses after they have received first-line platinum-based chemotherapy. Both trials used docetaxel because this agent had shown significant activity in this patient population in single-arm phase II trials. The eligibility requirements for both trials were also very similar, resulting in similar groups of patients being entered into each trial. Patients could have received more than one previous chemotherapy regimen, but 65 to 77% of the patients entered into these studies had received only one regimen. In the trial of Shepherd et al,65 previous treatment with a taxane was also an exclusion criteria. The majority of patients had a good PS (ECOG level 0 to 1 in 75 to 83% of patients), had stage IV NSCLC (80 to 90%), and were men (72 to 82%).

The first trial compared two doses of docetaxel (100 mg/m2 and 75 mg/m2 every 3 weeks) to BSC in patients who were taxane-naïve but had previously been treated with a platinum-based regimen. The original design was a two-arm trial comparing docetaxel, 100 mg/m2, to BSC. The trial was halted when a 6% death rate was noted in 49 patients secondary to febrile neutropenia. Also, a median of only two cycles of therapy was delivered. The dose of docetaxel was subsequently reduced to 75 mg/m2. At this dose, the median number of cycles delivered was four, and no febrile neutropenic deaths occurred. In an analysis of all patients, both the median survival times (chemotherapy arm, 7.0 months; BSC arm, 4.6 months) and the 1-year survival rates (chemotherapy arm, 29%; BSC arm, 19%) were significantly better for patients receiving second-line docetaxel vs those receiving BSC (p = 0.047 [log rank test]). The median survival time and the 1-year survival rate for the patients treated with docetaxel, 75 mg/m2, were 7.5 months and 37%, respectively (p = 0.003 compared to BSC). The overall response rate was 7.1%, with 42.7% of patients having disease stabilization on treatment. Clinical benefit was shown in a QOL study68 in which all QOL parameters favored the docetaxel-treated patients. Specifically, a significant reduction in pain and fatigue scale scores among the docetaxel-treated patients and a reduction in the need for narcotics, nonmorphine analgesic agents, and radiotherapy were documented in this group of patients.

The second trial randomized 373 patients who had previously received platinum-containing chemotherapy to one of the three following arms: docetaxel, 100 mg/m2; docetaxel, 75 mg/m2; or a control regimen of either vinorelbine or ifosfamide (V/I). The overall response rates were 6.7 to 10.8% among patients in the two docetaxel arms vs 0.8% among patients in the V/I arm (p < 0.05). The time to progression and the progression-free survival at 26 weeks also significantly favored patients in the two docetaxel arms. Although the median survival time was not significantly different between the groups, the 1-year survival rate was significantly greater with docetaxel, 75 mg/m2, (32%) compared to V/I (19%; p = 0.025). The 1-year survival rate for patients receiving docetaxel at 100 mg/m2 was 21%.

Several of the other new agents have been studied in the second-line setting, including paclitaxel, gemcitabine, irinotecan, and vinorelbine. In general, these trials have included small numbers of patients with variable results. Response rates have ranged from 0 to 20% and median survival rates (when reported) of 4 to 8 months. No randomized trials including these other agents exist with the exception of vinorelbine, as noted above.

A recent review recommended that patients with a good PS who are experiencing disease progression after receiving platinum-based chemotherapy should be offered second-line chemotherapy. Level of evidence, good; benefit, moderate; grade of recommendation, B.

H. Cho, Y.-B. Song, I.-S. Choi, E.-H. Cho, J.-W. Choi, Y. M. Ahn, Y. H. Roh, S.-H. Nam, and B.-S. Kim
A Phase II Study of Single-Agent Gemcitabine as a Second-Line Treatment in Advanced Non-Small Cell Lung Cancer
Jpn. J. Clin. Oncol., January 1, 2006; 36(1): 50 – 54.

M. A. Socinski, D. E. Morris, G. A. Masters, and R. Lilenbaum
Chemotherapeutic Management of Stage IV Non-small Cell Lung Cancer
Chest, January 1, 2003; 123(1_suppl): 226S – 243S.

Paris D. Makrantonakis, Eleni Galani, Peter G. Harper, Non-Small Cell Lung Cancer in the Elderly The Oncologist, Vol. 9, No. 5, 556-560, September 2004;

The issue of chemosensitivity testing is complex and controversial. The recent article by Schrag et al1 criticized the field of chemosensitivity and drug resistance, concluding that these types of in vitro assays are not yet ready for prime time. The panel of authors attempted to present evidence that in vitro drug response assays should not be used clinically. This issue was first addressed by an exhaustive Medicare Coverage Advisory Committee (MCAC) in 1999. A panel of physicians selected by the Department of Health and Human Services reviewed hundreds of articles from the literature and heard two days of testimony by experts in the field in an open hearing. The panel voted unanimously that although chemosensitivity assays should not be covered, drug resistance assays , a variety of testing for resistance to very high chemo concentrations rather than testing for sensitivity, should be paid for. This became a cause celebre with a vigorous debate in the literature and variant opinions offered by professional bodies. The American Society of Clinical Oncology vigorously objected and recommended: ”
The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient’s health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.” I believe that the So. California branch of ASCO with Dr. Wiesenthal dissented from this recommendation, see http://weisenthal.org/medicareletter.pdf.

In conclusion, the proposed assay is not supported by the near-total consensus of expert opinion or professional bodies. There are important dissenters, including some physicians and Medicare.

Rationale:

Schrag D, Garewal HS, Burstein HJ, et al: American Society of Clinical Oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol 22 : 3631 -3638, 2004

John P. Fruehauf In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins Journal of Clinical Oncology, Vol 23, No 15 (May 20), 2005: pp. 3641-3643

P. Hwu, A. Y. Bedikian, and E. A. Grimm
Challenges of chemosensitivity testing.
Clin. Cancer Res., September 15, 2006; 12(18): 5258 – 5259.

M. Markman Chemosensitivity and Chemoresistance Testing
J. Clin. Oncol., October 10, 2005; 23(29): 7363 – 7364.

R. Nagourney Chemosensitivity and Resistance Assays: A Systematic Review?
J. Clin. Oncol., May 20, 2005; 23(15): 3640 – 3641.

J. P. Fruehauf and D. S. Alberts
In Vitro Drug Resistance Versus Chemosensitivity: Two Sides of Different Coins
J. Clin. Oncol., May 20, 2005; 23(15): 3641 – 3643.

H. S. Wieand
Chemotherapy Sensitivity and Response Assays: Are the ASCO Guidelines for Clinical Trial Design Too Restrictive?
J. Clin. Oncol., May 20, 2005; 23(15): 3643 – 3644.

M. Castro Resisting a Fundamentalist Policy
J. Clin. Oncol., May 20, 2005; 23(15): 3645 – 3646.

Neoadjuvant therapy for locally advanced non-small cell lung cancer has evolved rapidly near the turn of the century. Historically, radiation used to be the only treatment for unresectable non-small cell lung cancer. In 1990, Dillman et al introduced the use of neoadjuvant cisplatin-based chemotherapy before radiation with better survival, and other chemotherapy regimens used in this fashion also yielded comparable results. Nevertheless, adding adjuvant chemotherapy after radiation provided no additional benefit. Subsequently, the use of neoadjuvant chemotherapy followed by radiation waned, when concurrent chemoradiation had been found to produce better survival outcome. Today, concurrent chemoradiation is the standard of care for patients with unresectable non-small cell lung cancer who have good performance status.

In certain situations, concurrent chemoradiation has transformed its role from a definitive treatment into a neoadjuvant treatment before radical resection. Concurrent chemoradiation may render some unresectable non-small cell lung cancers resectable. Although no data from randomized, controlled trials are available, it is evident that patients with superior sulcus tumor or pancoast tumor, after undergoing neoadjuvant radiation with or without concurrent chemotherapy, may become eligible for complete resection and achieve prolonged disease-free survival.

For patients with resectable but locally advanced non-small cell lung cancer, outcome of treatment with surgery alone is poor. Several small, randomized studies suggest that neoadjuvant chemotherapy before surgery improves overall survival when compared with surgery alone. One such study, for instance, using 3 cycles of chemotherapy followed by surgery, demonstrated an increase in median survival from 8 months in the surgery-alone arm to 26 months in the neoadjuvant arm. Subsequent larger studies, however, produced conflicting results. Other investigators have experimented with concurrent chemoradiation followed by surgery in comparison with chemoradiation alone.[48] Preliminary data indicate that patients who respond well to chemoradiation may benefit from subsequent surgery, although long-term follow-up is still necessary.
Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 1999;17:2692-2699.

1. Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg 2001;121:472-483.

   nccn.org, lung cancer

Approximately 80,000 patients will be diagnosed with either stage II or stage III colon cancer in 2007. Although some controversy still exists regarding the role of adjuvant therapy for patients with stage II disease (but newer studies are beginning to show benefit even is stage II), studies have confirmed the benefits of treatment for those with stage III disease.

The use of DFS as a primary endpoint in colon cancer adjuvant trials was further demonstrated by the updated results of the MOSAIC [Multi-center International Study of Oxaliplain/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer] trial, which compared the benefit of adding oxaliplatin to 5-FU/leucovorin (LV) (FOLFOX 4) as adjuvant treatment compared with 5-FU/LV alone. The 3-year DFS with FOLFOX 4 was 78.2% vs 72.9% for 5-FU/LV alone (hazard ratio [HR] = 0.77; P = .002). At 5 years, overall survival remained superior with FOLFOX 4 (73.3% vs 67.4%; HR = 0.80; P = .03). The survival benefit (82.1% vs 74.9 %; HR = 0.74) was seen primarily in “high-risk” patients with stage II disease (ie, T4, bowel obstruction/perforation, poorly differentiated tumors, venous invasion, or fewer than 10 examined nodes) and in those with stage III disease (66.4% vs 58.9%; HR = 0.78; P = .005). The addition of oxaliplatin did not appear to benefit patients with low-risk stage II disease. Median follow-up at 6 years revealed that the benefit of FOLFOX 4 was confined to patients with stage III disease: 73.0% vs 68.6%; HR = 0.8; P = .029. For those with stage II disease, survival at 6 years was equivalent, nearly 87% with either 5-FU/LV or FOLFOX 4.

Toxicities associated with oxaliplatin, such as neutropenia, were common (41%), but febrile neutropenia was uncommon (1.8%). Peripheral neuropathy developed in approximately 15% of patients, but grade 3 neuropathy was seen in only 0.7%, indicating significant recovery from the neurosensory effects of oxaliplatin in the vast majority of patients.

Sargent DJ, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. Time dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer. Lessons from the 20,800 patient ACCENT dataset. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4008. O’Connell MJ, for the Adjuvant Colon Cancer Endpoints (ACCENT) Group. Survival following recurrence in patients with adjuvant colon cancer: findings from the 20,800 patient ACCENT dataset. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4009. de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with median follow up of six years. Proc Am Soc Clin Oncol. 2007;25:165s. Abstract 4007. Wolmark N, Wieand S, Kuebler JP, Colangelo L, Smith RE. A phase III trial comparing 5FU/LV to 5FU/LV and oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP protocol C07. Proc Am Soc Clin Oncol. 2005;25:264s. Abstract LBA3500. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352:2696-2704