Toxicity Profile of VAD Regime in Patients with Multiple Myeloma

S R Dawnji,a R Reeja,b Rakesh Praveen Raj M R,c N Geethad

a. Department of Pharmacology, Government Medical College, Trivandrum; b. Department of Pharmacology, ESIC Medical College, Parippally, Kollam; c. Department of General Surgery, Travancore Medical College, Kollam; d. Department of Medical Oncology, Regional Cancer Centre, Trivandrum


Abstract

This longitudinal unicentric clinical study was done with the objective to study the spectrum, incidence and severity of toxicity among Multiple Myeloma patients receiving VAD regimen (Vincristine, Adriamycin and Dexamethasone) at Regional Cancer Centre, Trivandrum, Kerala.  BetweenNovember 2005 and November 2006, 42 adult patients with previously untreated Multiple Myeloma were assigned to receive VAD at Regional Cancer Centre, Trivandrum.  During chemotherapy, patients were followed-up to detect the development of any symptoms of toxicity.  The toxicities recorded, were graded according to the World Health Organization toxicity guidelines.

Among the 42 patients who received VAD, the most common toxicities encountered were gastrointestinal.  Peripheral neuropathy and infection were seen to a lesser extent, and haematological toxicities were low.

The VAD regimen was tolerated well by majority of the patients and showed favourable toxicity profile, reiterating its acceptability as a front line anti-myeloma regimen.

Keywords: , , ,

Introduction

Multiple myeloma is a neoplastic disease of B cell lineage resulting in abnormal proliferation of plasma cells1. Multiple myeloma accounts for 10% of all haematological malignancies and 1% of all malignancies. Treatment of myeloma includes conventional chemotherapy, high dose chemotherapy and stem cell transplant. The commonly used chemotherapy regimens in Multiple myeloma include VAD, MP, EP and THAL-DEX.

The development of chemotherapy for Multiple Myeloma began in 1950’s with the early use of alkylating agents like Melphalan and Cyclophosphamide2. This was followed by combination chemotherapy with Melphalan and Prednisolone which turned out to be the first successful chemotherapy for Multiple Myeloma3 offering 50% response rate and median survival of 2-3 years. In 1980’s Alexanian and colleagues from MD Anderson Hospital in Texas developed a new chemotherapeutic regimen – VAD. Vincristine and Adriamycin given as continuous infusion over 4 days with high dose Dexamethasone resulted in a rapid and high response rate, and a median duration of remission of 18 months. Advantage over other regimens is its utility in renal failure patients, as a preparation for autologous stem cell transplantation.4

 Aims and Objectives

  • To study the spectrum of toxicities due to chemotherapy with VAD regimen in patients newly-diagnosed with Multiple Myeloma
  • To study the incidence and the severity of these toxicities by grading them according to WHO guidelines

Materials and Methods

This was a longitudinal clinical study conducted at the Department of Medical Oncology, Regional Cancer Centre, Trivandrum, from November 2005 to November 2006, after obtaining institutional ethics committee approval. Patients with newly diagnosed Multiple Myeloma, aged  more than 21 years and planned for VAD regimen were included in the study.

After informed consent, a detailed history was taken and clinical examination was performed.  Results of baseline laboratory investigations prior to therapy were collected and recorded.  These included complete blood count, routine blood biochemistry, serum and 24-hour urine electrophoresis, serum Immunoglobulin, beta2 macroglobulin, C-reactive protein, ECHO and complete neurological evaluation. All of these were repeated before each cycle of chemotherapy.  X-ray, skeletal survey and bone marrow aspiration were repeated after 6 months of treatment.

Chemotherapy was administered according to the following schedule:

VAD Regimen

  • VINCRISTINE- 0.4 mg/m2, 1-4 days, continuous i/v infusion
  • ADRIAMYCIN- 9mg/m21-4 days, continuous i/v infusion
  • DEXAMETHASONE 40 mg OD on Days 1-4, 9-12 and 17-20 in a month

This is repeated every 4 weeks for 6 months. Administration of Bisphosphonates was allowed in this regimen.

During the course of chemotherapy regimen, patients were examined to detect any adverse drug reactions / toxicity symptoms. Laboratory test done during the course were reviewed for any abnormality. After recording toxicity they were graded according to WHO guidelines. The common toxicities looked for in this study were haematological, gastrointestinal, respiratory, cardiovascular, renal, dermatological, endocrine and infectious. 

Figure 1. Baseline clinical stages of Multiple Myeloma (Durie-Salmon) of study subjects

Figure 1. Baseline clinical stages of Multiple Myeloma (Durie-Salmon) of study subjects

Observations and Results

Forty-two patients with newly diagnosed multiple myeloma with a median age of 54 yrs (range 27-68) were enrolled in the study, from November 2005 to November 2006, and were scheduled to receive VAD protocol. Of these 26 (62%) were men and 16 were women.  Most patients were in the 2nd or 3rd clinical stage of multiple myeloma (Figure 1).

Table 1. Baseline Laboratory parameters of patients with Multiple Myeloma

Table 1. Baseline Laboratory parameters of patients with Multiple Myeloma

The baseline laboratory parameters of the patients are shown in Table 1. The treatment plan used according to the clinical assessment is shown in Table 2. Toxicity manifestations during treatment are listed in Table 3.

Discussion

First line treatment in Multiple myeloma aims primarily at high response rate and early reduction of tumor burden, achieved with the least possible toxicity to bone marrow stem cells, since High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) in eligible patients are by now the only therapeutic strategy that prolongs overall survival.5

Table 2. Treatment Plan with VAD according to clinical assessment

Table 2. Treatment Plan with VAD according to clinical assessment

So VAD, VAD like regimen, THAL-DEX and proteosome inhibitors, have replaced MP and has been widely  accepted as first line treatment in Multiple myeloma during the last decades, inducing early objective responses in 55-67% of patients.6,7,8

Table 3. Toxicity profile of patients with Multiple Myeloma on VAD

Table 3. Toxicity profile of patients with Multiple Myeloma on VAD

The limiting factor in the efficacy of any anticancer therapy is the grave toll that the side effects of therapy take on the patients. This has instigated investigators to constantly discover or innovate, new or existing therapies or combinations that can yield a high rate of response with a simultaneous reduction in the incidence and severity of side effects. In our study toxic manifestations of VAD regimen were in general tolerated well and mostly reversible.

Most of the patients in the study had a performance status of grade-1 at presentation. Haematological toxicities were well tolerated, never requiring temporary withdrawal of therapy. Anaemia was the most common haematological toxicity observed. During chemotherapy most patients had grade-1 (22 patients) in every cycle, grade-4 was the maximum toxicity in only 3 patients and required blood transfusion. Leucopenia and thrombocytopenia were not major toxicity issues (> grade-2= 0).

The most common metabolic derangement observed was hyperglycemia. During therapy, 12 patients developed hyperglycemia (Grade >2=8).  All patients required antidiabetic therapy. One patient developed diabetic ketoacidosis.

Unlike other chemotherapy regimens, gastrointestinal toxicity was not distressing to patients.  Anorexia, nausea, constipation and gastritis were the most common toxicities encountered in VAD, along with a few complaints of vomiting and stomatitis.  Even though anorexia and nausea were persistent problems for majority of patients on the VAD regimen (28 patients) none of the patients progressed beyond grade-2 toxicity.  The next common GIT toxicity observed was nausea. Twenty eight patients experienced nausea of which 26 had grade-1, with the maximum observed being grade-2 in 2 patients.  Gastritis and constipation were also frequently encountered in this regimen.  Of the 42 patients, 40 patients developed gastritis (grade-1, in 39 patients) and forty one developed constipation.  None of the patients progressed beyond grade-2 toxicity.  Vomiting was observed in only 12 patients under VAD, and none progressed beyond grade-1 toxicity.  Other minor toxicities observed were stomatitis (grade-1 in 10 patients), diarrhoea (self-limiting in 4 patients), abdominal distension and heartburn (15 patients).

Various studies showed that alopecia occurred in more than half of the patients receiving standard intermittent doses.  The dose per cycle appears to play some role. Frequent low doses are less likely to cause alopecia. Our study showed the development of alopecia in VAD regimen. Out of the 41 patients, majority showed grade-2 toxicity (29 patients) and 12 patients experienced grade-1. Interestingly, one patient remained unaffected during the entire chemotherapy.

Regarding pulmonary toxicity 8 patients developed upper respiratory tract infection. Minor toxicities like cough and dyspnoea, were noticed in 5 patients.

Cardiac toxicity in VAD regimen is attributed to Adriamycin. Three patients on VAD regimen developed cardiac toxicity which presented mainly as chest pain and palpitations. After first cycle, one patient developed unstable angina and was changed to another regimen. One patient developed chest pain with left bundle branch block during the fourth cycle. Another patient developed palpitations during the sixth cycle with ECHO showing diastolic dysfunction

Neurotoxicity was observed in few patients on this regimen, with predominantly sensory involvement than motor. Four diabetic patients developed sensory involvement (grade-1).  In this regimen sensory involvement occurred only in diabetic patients.

Majority of patients developed pigmentation of skin, nails and mucosa (grade-1).  Fourteen patients developed local toxicity at the site of drug administration – six developed pain and erythema (grade-1), and another six patients developed grade-2 phlebitis.  Two patients developed grade-2 ulceration of hand due to extravasation of Vincristine. Oedema was not noticed with this regimen.

Grade-1 infection was seen in 2 patients. Two patients developed neutropenic sepsis and was treated according to hospital protocol.  One patient developed otitis media which was treated with antibiotics.  Fifteen patients developed fever (G-1).  Myalgia and muscle cramps were minor complaints.  Seven patients on VAD regimen developed dry skin.

One patient developed jaundice and altered liver function.  Renal function was satisfactory in all patients

One patient developed generalized tonic clonic seizure after the first cycle due to metabolic disturbance, another patient developed blurring of vision and fundal examination revealed exudates in macula densa.  Two patients developed menstrual irregularities during the chemotherapy.  There was no mortality under this regimen.                              .

Conclusion

VAD is an effective antimyeloma regimen with favorable toxicity profile and may be considered as front line therapy for multiple myeloma patients who are candidates for autologous transplantation.  However the survival of patients on these regimens could not be assessed and this has to be determined by doing a study of longer duration. A drawback of this study is the small number of patients studied.  By increasing the number of patients and the duration of the study, the comparison of the toxicity profile and survival can be assessed.

References

  1. Robert A. Vesico, James R Bernson. Myeloma, Macroglobulinemia and amyloidosis-Cancer treatment-Haskell 5th edition; 99:1503-1539
  2. Gareth Morgan and Peter Selby-Myeloma-Oxford Textbook of Oncology, 2nd edition; 15-12:2419-2455
  3. Alexanian R., Bonnet J, Gehan E. et al. Combination chemotherapy for multiple myeloma. Cancer 1972; 30:382
  4. Samson D, et al. Infusion of Vincristine and Doxorubicin with oral Dexamethasone as first line therapy for myeloma. Lancer 1989; 2(8668): 882-5
  5. Vincent T, Divetta, Samuel Hellman, Steva A. Rosenberg. Antiangiogenesis agents: Cancer Principles and Practice of Oncology.6th edition; 63:2765-2770.
  6. Attal M, Harousseau JL, Stoppa AM et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in Multiple Myeloma. NEJM 1996; 336:91-97.
  7. Bardos A, Barlogie B, Siegel E et al .Autologous stem cell transplantation in elderly multiple myeloma patients over the age of 70 years.Br J Haematol 2001;114:600-607
  8. Hussien MA, Wood L, Hsi E et al. Phase II trial of pegylated liposomal doxorubicin, Vincristine, and reduced-dose Dexamethasone combination therapy in newly diagnosed myeloma patients. Cancer 2002;95:2160-2168.

Author Information 

  1. S R Dawnji, Assistant Professor, Department of Pharmacology, Government Medical College, Trivandrum. Email: dawnjisr@yahoo.co.in
  2. R Reeja, Associate Professor, Department of Pharmacology, ESIC Medical College, Parippally, Kollam. Email: drreejapraveen@gmail.com
  3. Rakesh Praveen Raj M R, Professor, Department of General Surgery, Travancore Medical College, Kollam.   Email: drrakeshpraveenraj@gmail.com
  4. N Geetha, HOD, Department of Medical Oncology, Regional Cancer Centre,    Trivandrum.   Email: geenarayanan@yahoo.com

Acknowledgements

Department and institution to which the work is attributed: Department of Medical Oncology, Regional Cancer Centre, Trivandrum

Conflict of Interest: None declared

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